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Nocardia Species
PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
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Nocardia Species Ellen Gould Chadwick and Richard B. Thomson, Jr.
Since the first reported case of human nocardiosis in 1890, Nocardia spp. increasingly have been recognized as serious human pathogens. Molecular analysis identified 80 species in the Nocardia genus, with ongoing evolution in the understanding of Nocardia taxonomy.1,2 Although challenging, identification of Nocardia isolates to the species level is important to determine pathogenicity and predict antimicrobial susceptibility.1 The more common clinical isolates reported by laboratories in past decades as Nocardia asteroides have been divided into six groups based on unique antimicrobial susceptibility patterns. Initially referred to as N. asteroides complex groups I to VI, all six groups are valid taxonomic clusters by gene sequencing and are given species or complex names. Although not a recognized taxonomic designation, N. asteroides complex is used for convenience to refer to all six groups. The term complex, when used with one of the six species groups, refers to a cluster of multiple but similar strains that have not been studied adequately to name all as individual species (Table 136.1). Current designations for the N. asteroides complex are N. abscessus complex, N. brevicatena-N. paucivorans complex, N. nova complex, N. transvalensis complex, N. farcinica, and N. cyriacigeorgica.2–4 The N. farcinica and N. cyriacigeorgica groups each contain closely related strains that represent a single species. Using the new taxonomy, most clinically significant isolates are N. cyriacigeorgica, N. farcinica, N. abscessus complex, or N. nova complex.2,5 Human non–N. asteroids complex pathogens usually are N. brasiliensis or N. otitidiscaviarum complex (formerly N. caviae). N. brasiliensis has been subdivided into N. brasiliensis and N. pseudobrasiliensis. Whereas N. brasiliensis infections often are limited to skin and subcutaneous tissue in healthy individuals, all species have been reported in pulmonary and systemic infections.3,6–10
MICROBIOLOGY The family Nocardiaceae is composed of aerobic actinomycetes and characterized by filamentous growth with true branching. Nocardia spp. are catalase- and urease-positive organisms that grow on multiple media, including Sabouraud dextrose agar, Löwenstein–Jensen medium, brainheart infusion agar, and simple blood agar. Although growth occurs over a wide temperature range, human pathogenic Nocardia spp. grow best at
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TABLE 136.1 Changing Classification of Medically Relevant Nocardia Species Current Classification
Classification Circa 1990–2000
Classification Before 1990
Nocardia abscessus complexa
Nocardia asteroides complex group I
Nocardia asteroides
Nocardia brevicatenapaucivorans complexa
Nocardia asteroides complex group II
Nocardia asteroides
Nocardia nova complexa
Nocardia nova (group III)
Nocardia asteroides
Nocardia transvalensis complexa,b
Nocardia asteroides complex group IV
Nocardia asteroides
Nocardia farcinica
Nocardia farcinica (group V)
Nocardia asteroides
Nocardia cyriacigeorgica
Nocardia asteroides complex group VI
Nocardia asteroides
Nocardia otitidiscaviarum complexa
Nocardia otitidiscaviarum
Nocardia caviae
Nocardia brasiliensis
Nocardia brasiliensis
Nocardia brasiliensis
Nocardia pseudobrasiliensis
Nocardia pseudobrasiliensis
Nocardia brasiliensis
a These taxa include diverse strains within the species groups. It is recommended that the term complex be used with the species names to indicate their heterogeneity and that the taxonomy eventually be more clearly defined.2 b N. wallacei is the most common species encountered in the N. transvalensis complex and is frequently referred to by N. wallacei rather than N. transvalensis complex. Data from References 1, 2, 43, 64.
Nocardia Species
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EPIDEMIOLOGY Nocardia are ubiquitous, saprophytic soil organisms that are easily aerosolized and found in house dust, garden soil, decaying vegetation, beach sand, fresh and salt water, and swimming pools. The lung is the primary portal of entry, and underlying pulmonary dysfunction with decreased bronchociliary clearance mechanisms (e.g., cystic fibrosis, asthma, bronchiectasis) predisposes to sporadic colonization, although infection rarely occurs in the absence of immunosuppression in patients with such dysfunction.5,12,13
PATHOGENESIS
FIGURE 136.1 Gram-stained smear (oil immersion objective, ×1000) of Nocardia sp. in purulent sputum specimen. Notice the filamentous, branching, beaded, or stippled gram-positive rods.
37°C in the presence of 10% carbon dioxide. Unlike most other Nocardia spp., N. farcinica grows as well at 45°C as it does at 35°C, and this property can be used to differentiate this species.11 Many selective (i.e., inhibitory) media used for isolation of pathogenic fungi do not support the growth of Nocardia spp. Colonies can appear within 48 hours when present in pure culture; in mixed culture from clinical specimens such as sputum, other organisms often obscure small Nocardia colonies, making it difficult to recognize the typical morphologic characteristics before 2 to 4 weeks of incubation. Laboratory personnel should be notified to observe cultures for 4 weeks when nocardiosis is being considered. Colonies can be smooth and moist or waxy; with further incubation, development of aerial hyphae causes a velvety or chalky appearance. Primary isolates usually are light orange, but the color can vary from cream to brick red. Microscopically, Nocardia spp. often are detected first on Gram stain, and they appear as delicately branched, weakly gram-positive organisms that tend to fragment into coccoid and bacillary elements (Fig. 136.1). Filaments show true branching, with irregular staining that creates a beaded appearance. Many Nocardia spp. are acid fast but retain fuchsin less avidly than Mycobacterium spp. Organisms from initial isolation are most reliably acid fast but become progressively less so on repeated subculture. A modified Ziehl-Neelsen or Kinyoun stain with the use of 1% sulfuric acid instead of acid alcohol for decoloration optimizes demonstration of acid-fast Nocardia in clinical specimens (Fig. 136.2).
Inhalation of Nocardia spp. can lead to primary pulmonary disease that resolves spontaneously or progresses to pneumonia. Disseminated infection occurs by hematogenous spread from the respiratory tract, especially in immunocompromised hosts. Primary cutaneous infections usually are the result of trauma with soil contamination of the wound, resulting in infection localized to the skin and subcutaneous tissue. Keratitis that is posttraumatic or associated with contact lens use and endophthalmitis have been reported.14–16 A few case clusters have been described, and person-to-person transmission has been documented on rare occasions.17,18 Patients with deficient host defenses, such as those with lymphoreticular malignancy, chronic obstructive pulmonary disease, chronic granulomatous disease, dysgammaglobulinemia, human immunodeficiency virus infection, or receiving corticosteroid therapy, are at high risk for invasive nocardiosis.5,7,9,13,19–21 Recipients of bone marrow or solid-organ transplants have a particularly high risk. In the latter group, high-dose corticosteroid therapy, a history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infections.22 There are many reports of Nocardia infections developing in adults treated with tumor necrosis factor inhibitors, especially infliximab.23,24 The host response to Nocardia consists of early neutrophil mobilization to localize infection; cell-mediated immunologic mechanisms then supervene, followed by killing of the organism by activated macrophages and cytotoxic T lymphocytes.25 As a facultative intracellular pathogen, the virulence of Nocardia is associated with the ability to inhibit phagosome-lysosome fusion in macrophages and to neutralize phagosomal acidification.9 Nocardia causes suppurative necrosis and abscess formation similar to that seen in pyogenic infection. Although tuberculoid granulomas and giant cells have been reported, lesions usually do not demonstrate granulomatous inflammation or tissue fibrosis. Confluent abscesses without capsules are characteristic, which may explain the frequency of dissemination from the primary pulmonary focus. Nocardia granules or grains, which are similar to the sulfur granules characteristic of actinomycosis, occasionally are found in superficial Nocardia infections but are absent in visceral infections.
CLINICAL MANIFESTATIONS
FIGURE 136.2 Modified acid-fast–stained smear (oil immersion objective, ×1000) of Nocardia sp. in the same purulent sputum specimen shown in Fig. 136.1.
The most common clinical manifestation is pulmonary disease, occurring in more than two thirds of cases. Infection causes acute, subacute, or chronic suppurative disease, which tends to remit and relapse. Acute onset with fever and systemic symptoms is uncommon. Pulmonary infection can manifest with cough or dyspnea and with nonspecific symptoms such as anorexia and weight loss. Hemoptysis occasionally occurs in the setting of cavitary disease. Untreated pulmonary nocardiosis mimics tuberculosis, with a chronic course that can resolve spontaneously, obscuring the source of subsequent metastatic infection. Chest radiographic findings vary and include bronchopneumonia, alveolar infiltrates, single or scattered nodules or abscesses, and interstitial reticular infiltrates. Cavitation or pleural involvement, or both, can occur. Widespread dissemination can occur, especially in solid-organ transplant recipients and other immunocompromised hosts. The central nervous system is the most common secondary site, where disease manifests as single or multiple brain abscesses. N. farcinica and N. otitidiscaviarum have been reported in brain abscesses with increasing frequency, which may have implications for treatment due to their antibiotic
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PART III Etiologic Agents of Infectious Diseases SECTION A Bacteria
resistance patterns.26–28 Nocardia also has been recognized as a cause of persistent neutrophilic meningitis despite negative routine cultures. Neurologic symptoms range from headache to coma with subacute or acute presentations. Neurotropism is so prominent a feature of nocardiosis that cranial imaging should be performed for patients with pulmonary infection even without the symptoms of central nervous system disease. Computed tomography (CT) or magnetic resonance imaging (MRI) typically shows a necrotic cavity surrounded by a contrast-enhancing smooth capsule of uniform thickness and surrounding edema, in contrast to the more irregular capsule seen in malignant tumors.26 T2-weighted MRI scans can show multiple concentric rings with various signal intensities.29 Skin manifestations of disseminated disease can be indistinguishable from primary cutaneous nocardiosis. Cutaneous lesions include cellulitis, pustules, ulcerations, pyoderma, subcutaneous abscesses, and mycetoma, which is a slowly progressive, often painless granulomatous mass associated with nodules, sinuses, and granules, usually involving the foot. Patients with skin involvement should be evaluated thoroughly to exclude disseminated disease. Subcutaneous abscesses, which are more nodular than fluctuant, do not have the same propensity for fistulous drainage as those caused by Actinomyces.8,30 A cervicofacial syndrome with cervical adenitis due to Nocardia has been described in children.31 Lymphocutaneous infection caused by N. brasiliensis can be indistinguishable from sporotrichosis manifesting as a primary ulcerative lesion at the site of injury, often on the lower extremity, with nodular lymphangitis, and it sometimes is associated with regional adenopathy and mild systemic symptoms.6,8,30 This syndrome also has been described at the site of a cat scratch.32 Nocardia can disseminate to most organs, including kidneys, intestine, pancreas, heart, spleen, liver, joints, bones, eye, spinal cord, thyroid, and adrenal glands.7,16,20,33,34 Organ infection with Nocardia spp. consists of single or multiple nodules or abscesses. Renal infection can cause dysuria, hematuria, or pyuria. N. brasiliensis arthritis in a healthy child without a history of penetrating injury was initially treated as juvenile idiopathic arthritis.35 Nocardia bacteremia is rare, but infections associated with central venous catheters (CVCs) and peritoneal dialysis catheters have been reported. Removal of the CVC followed by 3 months of antibiotic treatment has been successful in these cases.19,36,37 Limited case reports of nocardiosis in children suggest that clinical presentations are similar to those in adults.
LABORATORY FINDINGS AND DIAGNOSIS Nocardia spp. in tissue appear as branching, beaded, gram-positive filaments when stained by the Brown-Brenn modification of the Gram stain or other standard tissue Gram stain and Gomori methenamine-silver stain. Nocardia are not visible when stained with hematoxylin and eosin or periodic acid–Schiff stain. Identification in tissue can be confirmed using a modified acid-fast stain because Nocardia spp. are acid fast, but other branching, gram-positive rods are not. Although Nocardia grow best on antibiotic-free media, the rate of recovery can be enhanced using selective techniques to suppress rapidly growing organisms in specimens from skin or mucosal sites. Pretreatment with an acid wash and inoculation onto selective buffered charcoalyeast extract agar (as formulated for the detection of Legionella spp.) can increase the recovery of Nocardia from respiratory specimens.38 Although uncommon, N. asteroides complex strains can be isolated in automated blood culture systems, especially if patients are receiving immunosuppressive therapy. Performing blind subcultures on day 5 of incubation on negative specimens can increase recovery.39 When Nocardia infection is not suspected, cultures usually are discarded without terminal subculture or too early to allow growth of the organism. Usual laboratory biochemical methods can be used to differentiate N. asteroides complex, N. otitidiscaviarum complex, and N. brasiliensis; however, phenotypic testing does not identify the many species within the N. asteroides complex or the less common human pathogens within the genus.4,11,40 Definitive identification requires analysis of gene sequences by molecular methods (i.e., 16s rRNA gene and multilocus sequence analysis of 5–7 housekeeping genes have been most successful) and may be necessary for some patients with serious disease.1,2,4,41–43 Presumptive identification of a limited number of N. asteroides complex isolates can be provided using an abbreviated battery of tests.
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For example, N. farcinica is resistant to ceftriaxone, grows at 45°C, and opacifies Middlebrook agar, whereas N. cyriacigeorgica is susceptible to ceftriaxone, imipenem, and amikacin but resistant to ampicillin and erythromycin.1,44,45 Matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry is an emerging method for the identification of species.46 As the databases expand, full species identifications will be readily and accurately available. Performance of bronchoalveolar lavage in pulmonary disease or biopsy of an affected tissue site may be necessary when other clinical specimens are nondiagnostic, especially in immunocompromised hosts.
TREATMENT Clinical laboratory methods for the susceptibility testing of Nocardia spp. are standardized, with breakpoints established for interpretation.47–48 Although initial selection of antimicrobial therapy must be empiric, primary drug resistance exists. All clinical isolates should be tested.45,48 In a multisite reproducibility study, end-point determinations were especially difficult for ceftriaxone, imipenem, tigecycline, and sulfonamide. Specific caution for interpreting in vitro testing of N. cyriacigeorgica and N. transvalensis with ceftriaxone is warranted.49 Laboratories with little experience should consider sending isolates to reference laboratories for testing.3 A retrospective study of more than 750 Nocardia isolates sent to the Centers for Disease Control and Prevention from 1995 to 2004 found increasing resistance over time.50 Among the four most prevalent Nocardia species, TMP-SMX resistance ranged from 20% for N. brasiliensis to 80% for N. farcinica. Linezolid was the only antibiotic to which 100% of the isolates were susceptible. Resistance among all strains tested was lowest for amikacin (5%), imipenem (30%), and ceftriaxone (52%), although N. farcinica typically is resistant to the cephalosporins.3,51 In vitro studies have shown that meropenem is more active than imipenem against most Nocardia spp. but less active against N. farcinica and N. nova; in contrast, most Nocardia spp. are resistant to ertapenem.5,13,52,53 Amoxicillin-clavulanate is active against many strains of Nocardia, except N. nova, N otitidiscaviarum, and N. cyriacigeorgica, which are resistant.50–52 Moxifloxacin usually is more active than ciprofloxacin and was shown in one report to be successful in treating a N. farcinica brain abscess in an immunosuppressed patient.54 Data for 1299 clinical isolates confirm the excellent activity of amikacin and linezolid, document increasing resistance to imipenem (51% resistance), and report only 2% of all strains are resistant to TMP-SMX (0.5% resistance for N. farcinica).55 A sulfonamide always has been the treatment of choice for nocardiosis when used in conjunction with appropriate surgical drainage or excision of empyema or large abscesses. Trimethoprim-sulfamethoxazole (TMPSMX) is reportedly effective in many clinical series, supplanting sulfonamides as the treatment of choice of many experts.56 Reports of sulfonamide resistance or lack of effectiveness in immunosuppressed patients led most clinicians to use additional agents in combination with a sulfonamide, at least initially. Nephrotoxic interaction between TMP-SMX and cyclosporine may necessitate the use of alternative agents in organ transplant recipients.20 Thrice-weekly TMP-SMX used for prophylaxis against Pneumocystis jirovecii infections frequently is ineffective in preventing nocardiosis.19,22 Because of linezolid’s excellent in vitro activity (i.e., minimal inhibitory concentration [MIC] <8 µg/mL for all strains of Nocardia) linezolid may be useful as initial therapy until speciation or susceptibility of the isolate is available.57 Although linezolid is approved only for short courses and is expensive, it has been used for longer-term therapy (with caution that long-term use can have adverse effects). Although clinical improvement can occur with single-drug therapy, two or three drugs with in vitro activity (preferably a combination demonstrating synergy, such as TMP-SMX with amikacin or a carbapenem) should be used for progressive disease, especially in immunocompromised hosts. Duration of therapy for nocardial infection depends on the site of infection and the immune status of the host. For primary cutaneous nocardiosis, a course of 6 to 12 weeks of sulfonamide therapy is appropriate, although spontaneous resolution of disease without therapy has been reported.58,59 For patients with isolated pulmonary disease, 6 to 12 months of therapy is preferred.60 Brain abscess or meningitis requires longer therapy, at least 12 months in most cases. A second or third drug
Key Points: Epidemiology, Clinical Syndromes, Diagnosis and Treatment of Nocardia Infections EPIDEMIOLOGY • Ubiquitous soil organisms • Lung is the primary portal of entry into the body. • Most infections occur in children with immunodeficiency (e.g., chronic granulomatous disease, HIV infection, chronic high-dose corticosteroid therapy, lymphoreticular malignancies, bone marrow and solid-organ transplantation, and dysgammaglobulinemia). CLINICAL SYNDROMES • Pulmonary infiltrates or abscesses with or without pleural effusion • Disseminated disease usually includes pulmonary and central nervous system infection, but any organ can be affected. • Primary cutaneous or lymphocutaneous infection results from direct inoculation. DIAGNOSIS • Tissue diagnosis (e.g., bronchoalveolar lavage, tissue biopsy) often is necessary. • Branching, beaded, gram-positive filaments using standard Gram staining procedures for tissue or smears • Modified acid-fast stain confirms identification because Nocardia spp. are weakly or partially acid fast, but other branching, gram-positive rods are not.
with proven activity in vitro, such as amikacin and ceftriaxone, usually is given for the first 4 to 12 weeks of treatment or until clinical and radiographic improvement is observed.5,13,60 Parenteral therapy should be used for the first 3 to 6 weeks, until a response to therapy has been documented and the species and its antibiotic susceptibilities have been determined; thereafter, oral therapy can be used to complete the course of treatment. Relapses after prolonged therapy occur but are uncommon. Lifelong suppressive therapy for nocardiosis is probably prudent in patients with acquired immunodeficiency syndrome and persistent, severe CD4+ T-lymphocyte depletion.51 Delayed appearance of metastatic abscesses, even during effective therapy, often represents the evolution of a previously seeded focus. Because infection by Nocardia can manifest concurrently with infection due to other opportunistic pathogens in immunocompromised patients, poor response to therapy or the development of new lesions should raise the possibility of a concomitant pathogen, such as Mycobacterium tuberculosis, P. jirovecii, or Aspergillus. Although older series report mortality rates of 44% to 85%, later published mortality rates range from 15% to 26%.5,12,20,61–63 Mortality rates for patients with cancer may be as high as 60%. Factors that increase mortality rates include concurrent corticosteroid or antineoplastic therapy and coinfection with cytomegalovirus.19 Consideration of nocardial infection in the differential diagnosis of immunocompromised or
• Selective media (e.g., selective buffered charcoal-yeast extract agar) may be necessary to prevent overgrowth of more rapidly growing contaminants in specimens from skin or mucosal sites. • Laboratory personnel should be notified to hold cultures for at least 2 weeks to allow for slow growth of Nocardia. • Definitive species identification requires gene sequencing, although MALDI-TOF mass spectrometry is emerging as a rapid and accurate alternative. • Standardized methods for in vitro antimicrobial testing are available. TREATMENT • Trimethoprim-sulfamethoxazole (TMP-SMX) has been the historical treatment of choice, but emergence of resistant strains dictates broader coverage. • Empiric combination therapy is used for pulmonary or disseminated disease, especially in immunocompromised hosts. ■ Two or three active agents are used, including TMP-SMX, linezolid, amikacin, carbapenem, and ceftriaxone. ■ Definitive therapy is guided by in vitro susceptibility tests. • Surgical debridement as adjunctive therapy is often required • Duration of therapy for invasive disease is 6 to 12 months or longer.
debilitated patients and aggressive diagnostic pursuit can lead to an earlier diagnosis and improved outcome. All references are available online at www.expertconsult.com.
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Nocardia Species
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J Clin Microbiol 1993;31:3040–3041. 45. Lowamn W, Aithma N. Antimicrobial susceptibility testing and profiling of Nocardia species and other anerobic actinomycetes from South Africa: comparative evaluation of broth microdilution versus the etest. J Clin Microbiol 2010;48:4534–4540. 46. Hsueh PR, Lee TF, Du SH, et al. Bruker biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry system for identification of Nocardia, Rhodococcus, Kocuria, Gordonia, Tsukamurella, and Listeria species. J Clin Microbiol 2014;52:2371–2379. 47. Clinical Laboratory and Standards Institute. Performance standards for antimicrobial susceptibility. Approved standard M100-S19. Wayne, PA, CLSI, 2009. 48. Woods GL. Susceptibility testing for mycobacteria. Clin Infect Dis 2000;31:1209–1215. 49. Conville PS, Brown-Elliott BA, Wallace RJ Jr, et al. Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species. J Clin Microbiol 2012;50:1270–1280. 50. Uhde KB, Pathak S, McCullum I Jr, et al. Antimicrobial-resistant Nocardia isolates, United States, 1995–2004. Clin Infect Dis 2010;51:1445–1448. 51. Lerner PI. Nocardiosis. Clin Infect Dis 1996;22:891–903. 52. Wallace RJ Jr, Brown BA, Tsukamura M, et al. Clinical and laboratory features of Nocardia nova. J Clin Microbiol 1991;29:2407–2411. 53. Yazawa K, Mikami Y, Ohashi S, et al. In-vitro activity of new carbapenem antibiotics: comparative studies with meropenem, L-627 and imipenem against pathogenic Nocardia spp. J Antimicrob Chemother 1992;29:169–172. 54. Fihman V, Berçot B, Mateo J, et al. First successful treatment of Nocardia farcinica brain abscess with moxifloxacin. J Infect 2006;52:e99–e102. 55. Schlaberg R, Fisher MA, Hanson KE. Susceptibility profiles of Nocardia isolates based on current taxonomy. Antimicrob Ag Chemother 2014;58:795–800. 56. Wallace RJ Jr, Septimus EJ, Williams TW, et al. Use of trimethoprim-sulfamethoxazole for treatment of infections due to Nocardia. Rev Infect Dis 1982;4:315. 57. Moylett EH, Pacheco SE, Brown-Elliott BA, et al. Clinical experience with linezolid for the treatment of Nocardia infection. Clin Infect Dis 2003;36:313–318. 58. Van Dijk K, van Kessel DA, Schijffelen MJ, et al. Disseminated Nocardia infection: spontaneous resolution in response to decrease of immunosuppression. New Microbes New Infect 2015;3:10–11. 59. King AS, Castro JG, Dow GC. Nocardia farcinica lung abscess presenting in the context of advanced HIV infection: spontaneous resolution in response to highly active antiretroviral therapy alone. Can J Infect Dis Med Microbiol 2009;20:e103–e106. 60. Martinez R, Reyes S, Menendez R. Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis. Curr Opin Pulm Med 2008;14:219–227. 61. Yildiz O, Alp E, Tokgoz B, et al. Nocardiosis in a teaching hospital in the Central Anatolia region of Turkey: treatment and outcome. Clin Microbiol Infect Dis 2005;11:493–512. 62. Pintado V, Gómez-Mampaso E, Fortun J, et al. Infection with Nocardia species: clinical spectrum of disease and species distribution in Madrid, Spain, 1978–2001. Infection 2002;30:338–340. 63. Matulionyte R, Rohner P, Uckay I, et al. Secular trends of Nocardia infection over 15 years in a tertiary care hospital. J Clin Pathol 2004;57:807–812. 64. Ruimy R, Riegel P, Carlotti A, et al. Nocardia pseudobrasiliensis sp. nov., a new species of Nocardia which groups bacterial strains previously identified as Nocardia brasiliensis and associated with invasive diseases. Int J Syst Bacteriol 1996;46:259–264.
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Nocardia Species Ellen Gould Chadwick and Richard B. Thomson, Jr.
Since the first reported case of human nocardiosis in 1890, Nocardia spp. increasingly have been recognized as serious human pathogens. Molecular analysis identified 80 species in the Nocardia genus, with ongoing evolution in the understanding of Nocardia taxonomy.1,2 Although challenging, identification of Nocardia isolates to the species level is important to determine pathogenicity and predict antimicrobial susceptibility.1 The more common clinical isolates reported by laboratories in past decades as Nocardia asteroides have been divided into six groups based on unique antimicrobial susceptibility patterns. Initially referred to as N. asteroides complex groups I to VI, all six groups are valid taxonomic clusters by gene sequencing and are given species or complex names. Although not a recognized taxonomic designation, N. asteroides complex is used for convenience to refer to all six groups. The term complex, when used with one of the six species groups, refers to a cluster of multiple but similar strains that have not been studied adequately to name all as individual species (Table 136.1). Current designations for the N. asteroides complex are N. abscessus complex, N. brevicatena-N. paucivorans complex, N. nova complex, N. transvalensis complex, N. farcinica, and N. cyriacigeorgica.2–4 The N. farcinica and N. cyriacigeorgica groups each contain closely related strains that represent a single species. Using the new taxonomy, most clinically significant isolates are N. cyriacigeorgica, N. farcinica, N. abscessus complex, or N. nova complex.2,5 Human non–N. asteroids complex pathogens usually are N. brasiliensis or N. otitidiscaviarum complex (formerly N. caviae). N. brasiliensis has been subdivided into N. brasiliensis and N. pseudobrasiliensis. Whereas N. brasiliensis infections often are limited to skin and subcutaneous tissue in healthy individuals, all species have been reported in pulmonary and systemic infections.3,6–10
MICROBIOLOGY The family Nocardiaceae is composed of aerobic actinomycetes and characterized by filamentous growth with true branching. Nocardia spp. are catalase- and urease-positive organisms that grow on multiple media, including Sabouraud dextrose agar, Löwenstein–Jensen medium, brainheart infusion agar, and simple blood agar. Although growth occurs over a wide temperature range, human pathogenic Nocardia spp. grow best at
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TABLE 136.1 Changing Classification of Medically Relevant Nocardia Species Current Classification
Classification Circa 1990–2000
Classification Before 1990
Nocardia abscessus complexa
Nocardia asteroides complex group I
Nocardia asteroides
Nocardia brevicatenapaucivorans complexa
Nocardia asteroides complex group II
Nocardia asteroides
Nocardia nova complexa
Nocardia nova (group III)
Nocardia asteroides
Nocardia transvalensis complexa,b
Nocardia asteroides complex group IV
Nocardia asteroides
Nocardia farcinica
Nocardia farcinica (group V)
Nocardia asteroides
Nocardia cyriacigeorgica
Nocardia asteroides complex group VI
Nocardia asteroides
Nocardia otitidiscaviarum complexa
Nocardia otitidiscaviarum
Nocardia caviae
Nocardia brasiliensis
Nocardia brasiliensis
Nocardia brasiliensis
Nocardia pseudobrasiliensis
Nocardia pseudobrasiliensis
Nocardia brasiliensis
a These taxa include diverse strains within the species groups. It is recommended that the term complex be used with the species names to indicate their heterogeneity and that the taxonomy eventually be more clearly defined.2 b N. wallacei is the most common species encountered in the N. transvalensis complex and is frequently referred to by N. wallacei rather than N. transvalensis complex. Data from References 1, 2, 43, 64.
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EPIDEMIOLOGY Nocardia are ubiquitous, saprophytic soil organisms that are easily aerosolized and found in house dust, garden soil, decaying vegetation, beach sand, fresh and salt water, and swimming pools. The lung is the primary portal of entry, and underlying pulmonary dysfunction with decreased bronchociliary clearance mechanisms (e.g., cystic fibrosis, asthma, bronchiectasis) predisposes to sporadic colonization, although infection rarely occurs in the absence of immunosuppression in patients with such dysfunction.5,12,13
PATHOGENESIS
FIGURE 136.1 Gram-stained smear (oil immersion objective, ×1000) of Nocardia sp. in purulent sputum specimen. Notice the filamentous, branching, beaded, or stippled gram-positive rods.
37°C in the presence of 10% carbon dioxide. Unlike most other Nocardia spp., N. farcinica grows as well at 45°C as it does at 35°C, and this property can be used to differentiate this species.11 Many selective (i.e., inhibitory) media used for isolation of pathogenic fungi do not support the growth of Nocardia spp. Colonies can appear within 48 hours when present in pure culture; in mixed culture from clinical specimens such as sputum, other organisms often obscure small Nocardia colonies, making it difficult to recognize the typical morphologic characteristics before 2 to 4 weeks of incubation. Laboratory personnel should be notified to observe cultures for 4 weeks when nocardiosis is being considered. Colonies can be smooth and moist or waxy; with further incubation, development of aerial hyphae causes a velvety or chalky appearance. Primary isolates usually are light orange, but the color can vary from cream to brick red. Microscopically, Nocardia spp. often are detected first on Gram stain, and they appear as delicately branched, weakly gram-positive organisms that tend to fragment into coccoid and bacillary elements (Fig. 136.1). Filaments show true branching, with irregular staining that creates a beaded appearance. Many Nocardia spp. are acid fast but retain fuchsin less avidly than Mycobacterium spp. Organisms from initial isolation are most reliably acid fast but become progressively less so on repeated subculture. A modified Ziehl-Neelsen or Kinyoun stain with the use of 1% sulfuric acid instead of acid alcohol for decoloration optimizes demonstration of acid-fast Nocardia in clinical specimens (Fig. 136.2).
Inhalation of Nocardia spp. can lead to primary pulmonary disease that resolves spontaneously or progresses to pneumonia. Disseminated infection occurs by hematogenous spread from the respiratory tract, especially in immunocompromised hosts. Primary cutaneous infections usually are the result of trauma with soil contamination of the wound, resulting in infection localized to the skin and subcutaneous tissue. Keratitis that is posttraumatic or associated with contact lens use and endophthalmitis have been reported.14–16 A few case clusters have been described, and person-to-person transmission has been documented on rare occasions.17,18 Patients with deficient host defenses, such as those with lymphoreticular malignancy, chronic obstructive pulmonary disease, chronic granulomatous disease, dysgammaglobulinemia, human immunodeficiency virus infection, or receiving corticosteroid therapy, are at high risk for invasive nocardiosis.5,7,9,13,19–21 Recipients of bone marrow or solid-organ transplants have a particularly high risk. In the latter group, high-dose corticosteroid therapy, a history of cytomegalovirus disease, and high levels of calcineurin inhibitors are independent risk factors for Nocardia infections.22 There are many reports of Nocardia infections developing in adults treated with tumor necrosis factor inhibitors, especially infliximab.23,24 The host response to Nocardia consists of early neutrophil mobilization to localize infection; cell-mediated immunologic mechanisms then supervene, followed by killing of the organism by activated macrophages and cytotoxic T lymphocytes.25 As a facultative intracellular pathogen, the virulence of Nocardia is associated with the ability to inhibit phagosome-lysosome fusion in macrophages and to neutralize phagosomal acidification.9 Nocardia causes suppurative necrosis and abscess formation similar to that seen in pyogenic infection. Although tuberculoid granulomas and giant cells have been reported, lesions usually do not demonstrate granulomatous inflammation or tissue fibrosis. Confluent abscesses without capsules are characteristic, which may explain the frequency of dissemination from the primary pulmonary focus. Nocardia granules or grains, which are similar to the sulfur granules characteristic of actinomycosis, occasionally are found in superficial Nocardia infections but are absent in visceral infections.
CLINICAL MANIFESTATIONS
FIGURE 136.2 Modified acid-fast–stained smear (oil immersion objective, ×1000) of Nocardia sp. in the same purulent sputum specimen shown in Fig. 136.1.
The most common clinical manifestation is pulmonary disease, occurring in more than two thirds of cases. Infection causes acute, subacute, or chronic suppurative disease, which tends to remit and relapse. Acute onset with fever and systemic symptoms is uncommon. Pulmonary infection can manifest with cough or dyspnea and with nonspecific symptoms such as anorexia and weight loss. Hemoptysis occasionally occurs in the setting of cavitary disease. Untreated pulmonary nocardiosis mimics tuberculosis, with a chronic course that can resolve spontaneously, obscuring the source of subsequent metastatic infection. Chest radiographic findings vary and include bronchopneumonia, alveolar infiltrates, single or scattered nodules or abscesses, and interstitial reticular infiltrates. Cavitation or pleural involvement, or both, can occur. Widespread dissemination can occur, especially in solid-organ transplant recipients and other immunocompromised hosts. The central nervous system is the most common secondary site, where disease manifests as single or multiple brain abscesses. N. farcinica and N. otitidiscaviarum have been reported in brain abscesses with increasing frequency, which may have implications for treatment due to their antibiotic
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resistance patterns.26–28 Nocardia also has been recognized as a cause of persistent neutrophilic meningitis despite negative routine cultures. Neurologic symptoms range from headache to coma with subacute or acute presentations. Neurotropism is so prominent a feature of nocardiosis that cranial imaging should be performed for patients with pulmonary infection even without the symptoms of central nervous system disease. Computed tomography (CT) or magnetic resonance imaging (MRI) typically shows a necrotic cavity surrounded by a contrast-enhancing smooth capsule of uniform thickness and surrounding edema, in contrast to the more irregular capsule seen in malignant tumors.26 T2-weighted MRI scans can show multiple concentric rings with various signal intensities.29 Skin manifestations of disseminated disease can be indistinguishable from primary cutaneous nocardiosis. Cutaneous lesions include cellulitis, pustules, ulcerations, pyoderma, subcutaneous abscesses, and mycetoma, which is a slowly progressive, often painless granulomatous mass associated with nodules, sinuses, and granules, usually involving the foot. Patients with skin involvement should be evaluated thoroughly to exclude disseminated disease. Subcutaneous abscesses, which are more nodular than fluctuant, do not have the same propensity for fistulous drainage as those caused by Actinomyces.8,30 A cervicofacial syndrome with cervical adenitis due to Nocardia has been described in children.31 Lymphocutaneous infection caused by N. brasiliensis can be indistinguishable from sporotrichosis manifesting as a primary ulcerative lesion at the site of injury, often on the lower extremity, with nodular lymphangitis, and it sometimes is associated with regional adenopathy and mild systemic symptoms.6,8,30 This syndrome also has been described at the site of a cat scratch.32 Nocardia can disseminate to most organs, including kidneys, intestine, pancreas, heart, spleen, liver, joints, bones, eye, spinal cord, thyroid, and adrenal glands.7,16,20,33,34 Organ infection with Nocardia spp. consists of single or multiple nodules or abscesses. Renal infection can cause dysuria, hematuria, or pyuria. N. brasiliensis arthritis in a healthy child without a history of penetrating injury was initially treated as juvenile idiopathic arthritis.35 Nocardia bacteremia is rare, but infections associated with central venous catheters (CVCs) and peritoneal dialysis catheters have been reported. Removal of the CVC followed by 3 months of antibiotic treatment has been successful in these cases.19,36,37 Limited case reports of nocardiosis in children suggest that clinical presentations are similar to those in adults.
LABORATORY FINDINGS AND DIAGNOSIS Nocardia spp. in tissue appear as branching, beaded, gram-positive filaments when stained by the Brown-Brenn modification of the Gram stain or other standard tissue Gram stain and Gomori methenamine-silver stain. Nocardia are not visible when stained with hematoxylin and eosin or periodic acid–Schiff stain. Identification in tissue can be confirmed using a modified acid-fast stain because Nocardia spp. are acid fast, but other branching, gram-positive rods are not. Although Nocardia grow best on antibiotic-free media, the rate of recovery can be enhanced using selective techniques to suppress rapidly growing organisms in specimens from skin or mucosal sites. Pretreatment with an acid wash and inoculation onto selective buffered charcoalyeast extract agar (as formulated for the detection of Legionella spp.) can increase the recovery of Nocardia from respiratory specimens.38 Although uncommon, N. asteroides complex strains can be isolated in automated blood culture systems, especially if patients are receiving immunosuppressive therapy. Performing blind subcultures on day 5 of incubation on negative specimens can increase recovery.39 When Nocardia infection is not suspected, cultures usually are discarded without terminal subculture or too early to allow growth of the organism. Usual laboratory biochemical methods can be used to differentiate N. asteroides complex, N. otitidiscaviarum complex, and N. brasiliensis; however, phenotypic testing does not identify the many species within the N. asteroides complex or the less common human pathogens within the genus.4,11,40 Definitive identification requires analysis of gene sequences by molecular methods (i.e., 16s rRNA gene and multilocus sequence analysis of 5–7 housekeeping genes have been most successful) and may be necessary for some patients with serious disease.1,2,4,41–43 Presumptive identification of a limited number of N. asteroides complex isolates can be provided using an abbreviated battery of tests.
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For example, N. farcinica is resistant to ceftriaxone, grows at 45°C, and opacifies Middlebrook agar, whereas N. cyriacigeorgica is susceptible to ceftriaxone, imipenem, and amikacin but resistant to ampicillin and erythromycin.1,44,45 Matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry is an emerging method for the identification of species.46 As the databases expand, full species identifications will be readily and accurately available. Performance of bronchoalveolar lavage in pulmonary disease or biopsy of an affected tissue site may be necessary when other clinical specimens are nondiagnostic, especially in immunocompromised hosts.
TREATMENT Clinical laboratory methods for the susceptibility testing of Nocardia spp. are standardized, with breakpoints established for interpretation.47–48 Although initial selection of antimicrobial therapy must be empiric, primary drug resistance exists. All clinical isolates should be tested.45,48 In a multisite reproducibility study, end-point determinations were especially difficult for ceftriaxone, imipenem, tigecycline, and sulfonamide. Specific caution for interpreting in vitro testing of N. cyriacigeorgica and N. transvalensis with ceftriaxone is warranted.49 Laboratories with little experience should consider sending isolates to reference laboratories for testing.3 A retrospective study of more than 750 Nocardia isolates sent to the Centers for Disease Control and Prevention from 1995 to 2004 found increasing resistance over time.50 Among the four most prevalent Nocardia species, TMP-SMX resistance ranged from 20% for N. brasiliensis to 80% for N. farcinica. Linezolid was the only antibiotic to which 100% of the isolates were susceptible. Resistance among all strains tested was lowest for amikacin (5%), imipenem (30%), and ceftriaxone (52%), although N. farcinica typically is resistant to the cephalosporins.3,51 In vitro studies have shown that meropenem is more active than imipenem against most Nocardia spp. but less active against N. farcinica and N. nova; in contrast, most Nocardia spp. are resistant to ertapenem.5,13,52,53 Amoxicillin-clavulanate is active against many strains of Nocardia, except N. nova, N otitidiscaviarum, and N. cyriacigeorgica, which are resistant.50–52 Moxifloxacin usually is more active than ciprofloxacin and was shown in one report to be successful in treating a N. farcinica brain abscess in an immunosuppressed patient.54 Data for 1299 clinical isolates confirm the excellent activity of amikacin and linezolid, document increasing resistance to imipenem (51% resistance), and report only 2% of all strains are resistant to TMP-SMX (0.5% resistance for N. farcinica).55 A sulfonamide always has been the treatment of choice for nocardiosis when used in conjunction with appropriate surgical drainage or excision of empyema or large abscesses. Trimethoprim-sulfamethoxazole (TMPSMX) is reportedly effective in many clinical series, supplanting sulfonamides as the treatment of choice of many experts.56 Reports of sulfonamide resistance or lack of effectiveness in immunosuppressed patients led most clinicians to use additional agents in combination with a sulfonamide, at least initially. Nephrotoxic interaction between TMP-SMX and cyclosporine may necessitate the use of alternative agents in organ transplant recipients.20 Thrice-weekly TMP-SMX used for prophylaxis against Pneumocystis jirovecii infections frequently is ineffective in preventing nocardiosis.19,22 Because of linezolid’s excellent in vitro activity (i.e., minimal inhibitory concentration [MIC] <8 µg/mL for all strains of Nocardia) linezolid may be useful as initial therapy until speciation or susceptibility of the isolate is available.57 Although linezolid is approved only for short courses and is expensive, it has been used for longer-term therapy (with caution that long-term use can have adverse effects). Although clinical improvement can occur with single-drug therapy, two or three drugs with in vitro activity (preferably a combination demonstrating synergy, such as TMP-SMX with amikacin or a carbapenem) should be used for progressive disease, especially in immunocompromised hosts. Duration of therapy for nocardial infection depends on the site of infection and the immune status of the host. For primary cutaneous nocardiosis, a course of 6 to 12 weeks of sulfonamide therapy is appropriate, although spontaneous resolution of disease without therapy has been reported.58,59 For patients with isolated pulmonary disease, 6 to 12 months of therapy is preferred.60 Brain abscess or meningitis requires longer therapy, at least 12 months in most cases. A second or third drug
Key Points: Epidemiology, Clinical Syndromes, Diagnosis and Treatment of Nocardia Infections EPIDEMIOLOGY • Ubiquitous soil organisms • Lung is the primary portal of entry into the body. • Most infections occur in children with immunodeficiency (e.g., chronic granulomatous disease, HIV infection, chronic high-dose corticosteroid therapy, lymphoreticular malignancies, bone marrow and solid-organ transplantation, and dysgammaglobulinemia). CLINICAL SYNDROMES • Pulmonary infiltrates or abscesses with or without pleural effusion • Disseminated disease usually includes pulmonary and central nervous system infection, but any organ can be affected. • Primary cutaneous or lymphocutaneous infection results from direct inoculation. DIAGNOSIS • Tissue diagnosis (e.g., bronchoalveolar lavage, tissue biopsy) often is necessary. • Branching, beaded, gram-positive filaments using standard Gram staining procedures for tissue or smears • Modified acid-fast stain confirms identification because Nocardia spp. are weakly or partially acid fast, but other branching, gram-positive rods are not.
with proven activity in vitro, such as amikacin and ceftriaxone, usually is given for the first 4 to 12 weeks of treatment or until clinical and radiographic improvement is observed.5,13,60 Parenteral therapy should be used for the first 3 to 6 weeks, until a response to therapy has been documented and the species and its antibiotic susceptibilities have been determined; thereafter, oral therapy can be used to complete the course of treatment. Relapses after prolonged therapy occur but are uncommon. Lifelong suppressive therapy for nocardiosis is probably prudent in patients with acquired immunodeficiency syndrome and persistent, severe CD4+ T-lymphocyte depletion.51 Delayed appearance of metastatic abscesses, even during effective therapy, often represents the evolution of a previously seeded focus. Because infection by Nocardia can manifest concurrently with infection due to other opportunistic pathogens in immunocompromised patients, poor response to therapy or the development of new lesions should raise the possibility of a concomitant pathogen, such as Mycobacterium tuberculosis, P. jirovecii, or Aspergillus. Although older series report mortality rates of 44% to 85%, later published mortality rates range from 15% to 26%.5,12,20,61–63 Mortality rates for patients with cancer may be as high as 60%. Factors that increase mortality rates include concurrent corticosteroid or antineoplastic therapy and coinfection with cytomegalovirus.19 Consideration of nocardial infection in the differential diagnosis of immunocompromised or
• Selective media (e.g., selective buffered charcoal-yeast extract agar) may be necessary to prevent overgrowth of more rapidly growing contaminants in specimens from skin or mucosal sites. • Laboratory personnel should be notified to hold cultures for at least 2 weeks to allow for slow growth of Nocardia. • Definitive species identification requires gene sequencing, although MALDI-TOF mass spectrometry is emerging as a rapid and accurate alternative. • Standardized methods for in vitro antimicrobial testing are available. TREATMENT • Trimethoprim-sulfamethoxazole (TMP-SMX) has been the historical treatment of choice, but emergence of resistant strains dictates broader coverage. • Empiric combination therapy is used for pulmonary or disseminated disease, especially in immunocompromised hosts. ■ Two or three active agents are used, including TMP-SMX, linezolid, amikacin, carbapenem, and ceftriaxone. ■ Definitive therapy is guided by in vitro susceptibility tests. • Surgical debridement as adjunctive therapy is often required • Duration of therapy for invasive disease is 6 to 12 months or longer.
debilitated patients and aggressive diagnostic pursuit can lead to an earlier diagnosis and improved outcome. All references are available online at www.expertconsult.com.
KEY REFERENCES 21. Dorman SE, Guide SV, Conville PS, et al. Nocardia infection in chronic granulomatous disease. Clin Infect Dis 2002;35:390–394. 22. Peleg AY, Husain S, Qureshi ZA, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 2007;44:1307–1314. 24. Ali T, Chakraburtty A, Mahmood S, Bronze MS. Risk of nocardial infections with anti-tumor necrosis factor therapy. Am J Med Sci 2013;346:166–168. 49. Conville PS, Brown-Elliott BA, Wallace RJ Jr, et al. Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species. J Clin Microbiol 2012;50:1270–1280. 55. Schlaberg R, Fisher MA, Hanson KE. Susceptibility profiles of Nocardia isolates based on current taxonomy. Antimicrob Ag Chemother 2014;58:795–800. 57. Moylett EH, Pacheco SE, Brown-Elliott BA, et al. Clinical experience with linezolid for the treatment of Nocardia infection. Clin Infect Dis 2003;36:313–318. 58. Van Dijk K, van Kessel DA, Schijffelen MJ, et al. Disseminated Nocardia infection: spontaneous resolution in response to decrease of immunosuppression. New Microbes New Infect 2015;3:10–11. 60. Martinez R, Reyes S, Menendez R. Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis. Curr Opin Pulm Med 2008;14:219–227.
Nocardia Species
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