Nocardia is a genus of widely distributed saprophytic bacteria that can cause opportunistic cutaneous/subcutaneous or pulmonary infections in domestic animals, wildlife, and humans following inoculation or inhalation, which can progress to systemic disease. Characteristic histologic or cytologic findings include suppurative to pyogranulomatous inflammation with branched, filamentous organisms with gram-positive and partially acid-fast staining characteristics. Special microbiological techniques and molecular diagnostic testing may be necessary for confirmation. Many months of targeted antimicrobial therapy based on culture and susceptibility results may be required. Prognosis is guarded in cases of disseminated disease.
Nocardia is a genus of widely distributed saprophytic bacteria that can cause opportunistic infections in domestic animals, wildlife, and humans. Mastitis, pneumonia, abscesses, and cutaneous/subcutaneous lesions are the major clinical manifestations of nocardiosis in production and companion animals. Diagnosis is challenging. Nocardiosis is usually refractory to conventional therapy.
Etiology of Nocardiosis in Animals
Nocardia spp belong to the class Actinobacteria (order Actinomycetales, family Nocardiaceae), a phylogenetically complex group of pathogens important to humans and animals that includes the genera Mycobacterium, Rhodococcus, Corynebacterium, and Actinomyces, which produce relatively similar clinical signs.
These aerobic actinomycetes are nonmotile, non–spore-forming, pleomorphic gram-positive, facultative intracellular organisms. In Gram-stained smears, Nocardia appears as rods, coccoid forms, or typical long or branching filaments, with a tendency to fragment into rods or pleomorphic organisms.
When cultured, some Nocardia spp produce aerial filaments. Colonies are smooth and mostly rugose, with a powdery surface and a variable number of colors (white, orange, yellow, red, or pink) because of the production of carotenoid-like pigments. Components of the cell wall, particularly mycolic acids, render Nocardia partially acid-fast. Pathogenic Nocardia spp are strictly aerobic, and they grow over a wide temperature range (10°C–50°C [50°F–122°F]).
Historically, Nocardia species identification has been based on phenotypic methods, including hydrolysis of different substrates (casein, xanthine, hypoxanthine, and tyrosine), carbohydrate assimilation (glucose, glycerol, galactose, glucosamine, inositol, adonitol, and trehalose), and antimicrobial susceptibility profile. According to this former classification, the most important pathogenic species for animals and humans were represented by the N asteroides complex (N asteroides, N nova, N farcinica), N brasiliensis, N pseudobrasiliensis, N otitidiscaviarum, and N transvalensis. However, diagnosis based exclusively on phenotypic assays may lead to misidentification of some species of Nocardia.
Speciation of Nocardia requires confirmation by molecular techniques. The advance of molecular methods has led to an extensive taxonomic reclassification and new characterization of species. Sequencing of 16S rRNA and other methods has enabled the naming of >90 Nocardia species, with >30 species reported as primary causes of opportunistic infections in humans and animals. Species formerly included in the N asteroides complex have been renamed as N nova,N abscessus, N farcinica, and N cyriacigeorgica (formerly N asteroides sensu stricto).
Epidemiology of Nocardiosis in Animals
Nocardiae are ubiquitous environmental saprophytes that degrade organic matter and can be found in soil, clay, dust, compost vegetation, freshwater and saltwater, and other environmental sources.
Nocardiosis is uncommon, although there has been an apparent increase in its occurrence in humans and animals worldwide. Natural infections in production and companion animals may be acquired via inhalation, ingestion, the intramammary route, or through traumatic percutaneous introduction of the pathogen. The occurrence of disease and Nocardia spp may vary geographically, influenced by animal management strategies and environmental factors (eg, dry, dusty, windy weather conditions).
Nocardia spp are a cause of environmentally derived mastitis in cattle and small ruminants. Nocardial mastitis usually affects dairy herds with a history of inadequate hygienic milking management or poor pre- and postmilking conditions. Mammary infections are caused predominantly by soil contamination of teat dips, udders, and milking equipment during washing procedures, in addition to inadequate hygienic conditions during intramammary infusion of drugs. Nocardia farcinica may survive in components used in intramammary therapy for >7 weeks, contributing to transmission of the pathogen from mammary quarter to quarter within an udder and from cow to cow within the herd. Dairy herds affected by nocardial mastitis also have a history of inappropriate concentrations of antiseptics in teat dips. Some outbreaks of nocardial mastitis have been reported to be related to dry-cow therapy or improper intramammary therapy procedures.
Transmission of the pathogen among companion animals is associated with inoculation through puncture wounds, foreign bodies, or secondary to bites, wounds, or scratches after cat fights. Rarely, canine nocardiosis has been related to inhalation of the bacterium. Canine and feline nocardiosis is strongly associated with underlying immunosuppressive disorders, particularly in dogs coinfected with canine morbillivirus (distemper virus) where the vaccination approach is inadequate and in cats infected by feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV). In dogs and cats, nocardiosis appears to affect mainly males. The feline disease is strongly associated with cutaneous abscesses or draining wounds caused probably by bites or scratches after fights, which may explain, in part, the male predisposition. In cats and dogs, clinical disease occurs independently of age, although canine nocardiosis has been reported mainly in animals < 2 years old.
Nocardiosis in horses is an opportunistic infection as well, and it is usually related to immune disorders. Most reported clinical cases of equine nocardiosis are marked by underlying immunosuppressive conditions, particularly pituitary pars intermedia dysfunction (PPID) or severe combined immunodeficiency in Arabian foals.
Pathogenesis of Nocardiosis in Animals
Pathogenicity of Nocardia spp in domestic animals is influenced by the virulence factors and growth phase of the strain, the structure of the bacterial cell wall, host susceptibility, route of transmission, coinfection with immunosuppressive diseases, underlying conditions, and development of pyogranulomatous or granulomatous inflammatory reaction. Nocardia are intracellular pathogens. The outcome of Nocardia infections is linked to the ability of the organism to resist the initial neutrophil and activated macrophage phagocytosis and cell-mediated immune response of the host. The organism possesses mycolic acids in the structure of the cell wall that increase resistance against phagocytosis by neutrophils and macrophages. Nocardia infections cause suppurative to pyogranulomatous inflammation, with fibrosis and necrosis of affected tissues.
The immune response against nocardial infections is primarily T cell–mediated. Nocardia organisms are able to inhibit phagosome-lysosome fusion into neutrophils and macrophages because of lipids and mycolic acids in the structure of the bacterial cell wall that mimic mycobacterial species. Nocardia is also resistant to acids, oxidative enzymes (catalase and superoxide dismutase), and other enzymatic mechanisms used by phagocytic cells. In addition, some toxins have been identified in Nocardia that appear to contribute to pathogenicity. The pathogen does not induce an effective humoral immune response mediated by the action of B lymphocytes.
Localized or cutaneous Nocardia infections usually induce suppurative lesions with a tendency to spread circumferentially. Nocardial mastitis usually is restricted to mammary parenchyma and supramammary lymph nodes. In contrast, pulmonary infections may lead to hematogenous dissemination of the pathogen, and development of lesions in other organs, including the brain, eye, liver, spleen, visceral lymph nodes, and kidneys.
Clinical Findings of Nocardiosis in Animals
A wide variety of clinical signs are recognized for Nocardia infections. Mastitis, cutaneous or subcutaneous lesions, abscesses in organs, mycetoma, and pneumonia are the most common clinical signs of nocardiosis among production and companion animals.
Nocardial Mastitis in Domestic Ruminants
Historically, N asteroides, N nova, and N otitidiscaviarum have been the most common species described in mammary nocardiosis of domestic ruminants, particularly dairy cows. Molecular-based methods have recognized other species as primary agents of mammary infections, with N farcinica and N neocaledoniensis reported in outbreaks of bovine mastitis in Canada and Italy, respectively. On the basis of 16S rRNA sequencing, N nova and N farcinica were the most common species detected in 80 cases of clinical and subclinical bovine mastitis in Brazil. Mammary infections caused by N puris, N veterana, N cyriacigeorgica, N arthritidis, and N africana have been less frequently reported.
Nocardial mastitis is an uncommon disease of domestic ruminants, characterized by acute or subacute onset of mammary swelling, loss of yield, and extensive suppurative to pyogranulomatous lesions with the destruction of tissue, and the tendency of chronic evolution. Most affected animals develop chronic infections that are refractory to conventional antimicrobial therapy. Subclinical infections can occur. Typically, clinical cases of mammary nocardiosis are observed in a few animals in the herd during lactation or dry period. Outbreaks of nocardial mastitis have been associated with contaminated intramammary therapy (eg, neomycin-containing products), along with milking or dry periods.
Clinical examination of the udder shows marked enlargement, edema, fibrosis, and either diffuse or multifocal palpable nodules (2–5 cm in diameter), occasionally with draining tracts. Strip cup testing reveals serous to purulent milk secretion and, rarely, small white to yellow particles (called “sulfur granules”), which are aggregates of bacteria (club colonies); however, sulfur granules are more typical of Actinomyces infections. High body temperature, anorexia, and rapid wasting of cows have also been observed. Infected cows have high milk somatic cell counts. Less frequently, the organism may disseminate from the mammary gland to other organs, causing regional lymphadenitis and pyogranulomatous or granulomatous foci.
Bovine Farcy
Traditionally, bovine farcy has been ascribed to N farcinica, an uncommon cause of chronic lymphangitis, lymphadenitis, and cutaneous nodules. However, considering that some mycobacteria (Mycobacterium farcinogenes and M senegalense) also have been associated with the disease, the etiology of bovine farcy remains to be fully elucidated. Initially, the lesions consist of small cutaneous nodules, predominantly in the leg and neck regions, which may enlarge and coalesce to lesions of up to 10 cm in diameter. Rarely, the nodules ulcerate. The lymphatic vessel has a cordlike aspect. Occasionally, the pathogen may disseminate, affecting internal organs and resembling tuberculosis. Bovine farcy is usually restricted to tropical regions.
Nocardiosis in Horses
Nocardiosis is an uncommon disease in horses. Most nocardial infections in horses have been described as involving species of the former N asteroides complex and occasionally N brasiliensis and N farcinica. On the basis of molecular assays, N nova was described as causing recurrent airway obstruction in a horse.
Severe pneumonia, pleuritis, disseminated abscesses in organs, cutaneous lesions, mycetomas, and, rarely, abortion are the main clinical signs of nocardiosis in horses. Systemic nocardiosis occurs via lymphohematogenous dissemination of the bacterium, causing abscesses in various organs. Clinical signs in cases of pulmonary nocardiosis include increased respiratory rate, cough, labored breathing, and nasal secretion. Cutaneous and subcutaneous lesions typically occur after the traumatic introduction of Nocardia into the skin, leading to suppurative to pyogranulomatous dermatitis, cellulitis, and cutaneous nodules located anywhere in the body, usually of circumscribed aspect. The lesions may ulcerate and have an odorless, white-yellowish to gray discharge. Mycetomas are another type of cutaneous infection, consisting of chronic and progressive skin lesions secondary to transcutaneous inoculation of Nocardia. Painless, purulent-to-necrotic nodules (primary mycetoma and secondary nodules) that drain purulent discharge through the sinus tract have been reported.
Nocardial abortion rarely occurs in mares. Two cases were recorded in Arabian and Thoroughbred mares at ~6 months of gestation, both with a history of failure to maintain gestation to term. Examination of the fetal remains revealed lesions in the liver and lung as well as the placenta. Species of the former N asteroides complex were cultured from the uterus of the Arabian mare. The term "nocardioform placentitis" is used to described some cases of equine placentitis and sporadic abortion caused by gram-positive branching filamentous actinomycetes.
Nocardiosis in Companion Animals
Species of the former N asteroides complex, N brasiliensis, N otitidiscaviarum, and N nova are the most frequent species of Nocardia described in dogs and cats. Molecular methods have identified N africana, N elegans, N jiangxiensis, and N tenerifensis in cats. Nocardia abscessus, N asiatica, N pseudobrasiliensis, and N veterana have been reported in dogs. Nocardia otitidiscaviarum, N cyriacigeorgica, N nova, and N farcinica have been reported in both dogs and cats. Molecular techniques have identified N nova, N cyriacigeorgica, N farcinica, and N veterana among 11 dogs from Brazil that had different clinical signs; N africana, N nova, and N veterana were identified from 3 cats.
Superficial skin, lymphocutaneous, and thoracic infections, as well as disseminated forms, have been described as the major clinical manifestations of canine and feline nocardiosis. Cutaneous or subcutaneous abscesses with fistulous tracts, ulcers, mycetomas, sero- to sanguinopurulent exudates, and regional lymphadenitis are frequent clinical manifestations of canine Nocardia infections. In cats, nocardial infections are associated predominantly with skin or lymphocutaneous lesions. Canine and feline infections both resemble human nocardiosis. Skin lesions occur mainly in the extremities, flank, nose, and neck areas.
Canine and feline pulmonary nocardiosis is characterized by anorexia, hyperthermia, mucopurulent oculonasal discharge, weight loss, cough, respiratory distress, and hemoptysis. Other disseminated forms of the disease in companion animals are indicated by abscesses or lesions in 2 or more sites (eg, liver, kidneys, spleen, eyes, bones, joints, and abdominal lymph nodes). Peritonitis, pleuritis, and pyothorax occur as systemic disseminations of the pathogen as well. Alimentary tract infection can cause gingivitis, halitosis, and ulceration of the oral cavity. Rarely, the organism affects the urinary tract and heart. Nocardial infection in the CNS is associated with seizures and deficits in proprioceptive reflexes.
Miscellaneous Nocardial Disease
Bovine or equine oral infection by Nocardia after ingestion of fibrous foods can lead to the development of suppurative lesions in the jaw. Sporadic cases of abortion have been reported in sows and cows. Submandibular, supramammary, and mesenteric lymphadenitis have been described in cows and pigs. Nocardiosis commonly causes organ abscesses and respiratory involvement in wildlife, including whales, dolphins, fish, and birds.
Diagnosis of Nocardiosis in Animals
Microbiological culture
Hematologic and imaging findings
Serologic testing
Molecular diagnosis
Pathological findings
Routine diagnosis of nocardiosis is based on epidemiological findings, clinical signs, and microbiological examination. Samples of abscesses, skin, synovial and pleural fluid, tracheobronchial lavage, milk, liquor, aspirates, organs (lymph nodes, liver, lung, kidney, uterus, placenta), or other tissues have been cultured on sheep blood or Sabouraud agar, incubated aerobically for 3–7 days at 37°C (98.6°F ) or 25°C (77°F), respectively. Growth of some Nocardia spp in culture media is slow, and incubation should be extended for at least 7 days on sheep blood agar and up to 14 days on Sabouraud agar. Colonies in sheep blood and Sabouraud agar are circular, convex, smooth or rough, firmly adherent to agar surface, odorless, and commonly nonhemolytic (blood agar), with various carotenoid-like pigments (cream, white, orange, pink, or red). Nocardia spp grow as typical powdery and dry surface colonies, resembling fungal organisms.
Gram-positive, typically branching filamentous organisms with a tendency toward fragmentation (formation of aerial or pseudohyphae) are evident by microscopic examination. Modified Ziehl-Neelsen (MZN) stain shows partially acid-fast organisms. Fine-needle aspiration, direct cytology, and biopsy have been used in diagnosis of nocardiosis, particularly involving skin lesions, in companion and production animals. Gram, Giemsa, and panoptic stains show a typical aggregate of branching organisms in aspirated clinical specimens.
Courtesy of Dr. Márcio Garcia Ribeiro.
Courtesy of Dr. Márcio Garcia Ribeiro.
Leukograms reveal mainly neutrophilic leukocytosis with left shift and monocytosis, while erythrograms show moderate nonregenerative anemia. Radiographs of dogs and cats with thoracic infections show focal or multiple masses, lobar consolidation, pleural effusion, and bronchointerstitial to alveolar infiltrates; whereas extrapulmonary abnormalities include nodules, abscesses, and lymphadenomegaly. For suspected nocardial infections in production and companion animals, other actinobacteria should be considered as differential diagnoses because of the similarities in some microbiological properties and clinical signs. Face and jaw enlargement caused by bovine and equine nocardiosis should be distinguished from infection by Actinomyces bovis (actinomycosis), Actinobacillus lignieresii (actinobacillosis), Staphylococcus aureus (botryomycosis), or Trueperella pyogenes, whereas canine nocardiosis requires differentiation from actinomycosis.
Serologic (immunodiffusion, ELISA, and complement fixation) and cutaneous hypersensitivity tests have been proposed to diagnose bovine and canine nocardiosis, although host animals usually develop a nonspecific antibody response against Nocardia—a fact that limits the use of serologic tests in routine diagnosis. Despite similarities in cell wall structure between nocardiae and mycobacteria, animals infected naturally by Nocardia show no cross-reaction to the tuberculin skin test.
Molecular-based methods have been used to confirm the phenotypic diagnosis of Nocardia spp. Examples include conventional and real-time PCR (qPCR) assay, pulse-field gel electrophoresis (PFGE), restriction fragment length polymorphism (RFLP) analysis ofgenes encoding 16S rRNA, heat shock protein (hsp65), essential secretory protein A (secA1), RNA polymerase B (rpoB), and gyrase B (gyrB), as well as multilocus sequence typing (MLST), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), gene sequencing, and DNA-DNA hybridization. These molecular techniques offer a time-saving, reliable, and valuable means of diagnosis and speciation, which has provided several taxonomic changes and the identification of new species of Nocardia.
Grossly, postmortem examination of mammary tissue, visceral organs, and other tissues reveals diffuse fibrosis, abscesses containing a great amount of pus or numerous small to large nodules and discrete to coalescing exudates with white or gray to reddish-brown color. Histologic findings are characterized by suppurative to pyogranulomatous inflammation, and less frequently granulomatous reaction, with focal areas of necrosis and clusters of typical branching filamentous organisms. The lesions show a suppurative, necrotic center containing branching filamentous organisms surrounded by macrophages, neutrophils, lymphocytes, and plasma cells. Epithelioid and multinucleated giant cells may be found as well. Characteristic small, soft yellow-white granules (called “sulfur granules”), formed by microcolonies of the organism surrounded by inflammatory cells, are sometimes evident in discharges of lesions. Regional lymph nodes that drain the lesions may be enlarged, with a firm to fluctuant consistency.
Treatment of Nocardiosis in Animals
Antimicrobial therapy
Surgical drainage, resection, or debridement of lesions
Supportive care
Nocardia infections in domestic animals and humans are usually refractory to conventional therapy because of the intracellular location of the pathogen, development of pyogranulomatous to granulomatous lesions, and resistance pattern of isolates to conventional antimicrobials.
Antimicrobial susceptibility profile varies markedly between Nocardia spp from different geographic areas. The Clinical and Laboratory Standards Institute approved an in vitro standardized susceptibility test for Nocardia by broth microdilution, although a modified disc diffusion method has been used as well. However, in vitro antimicrobial susceptibility testing does not always predict clinical response or cure in vivo.
Trimethoprim-sulfonamide, aminoglycosides (amikacin, gentamicin), amoxicillin-clavulanate, imipenem-cilastatin, some cephalosporins (ceftiofur, cefuroxime, cefotaxime, ceftriaxone), clarithromycin, and imipenem appear to be first-choice drugs for nocardiosis treatment in animals and humans. In addition, ampicillin, linezolid, doxycycline, erythromycin, and minocycline are described as alternative drugs for the treatment of animals. Clinical experience has shown improved outcomes when combined antimicrobial therapy is administered. Combination of amikacin or imipenem with sulfonamides or combination of amikacin with imipenem or cephalosporins (eg, cefotaxime or ceftriaxone) has been proposed to treat domestic animals. Intramammary infusions of trimethoprim-sulfonamide, cephalosporins, or aminoglycosides (ie, gentamicin) have been used for 5–7 days to treat bovine and goat nocardial mastitis, with relative success.
Long-term treatment of nocardiosis (1–6 months in domestic animals) is required because of clinical relapses after short-term protocols. In companion animals, surgical procedures (debridement, drainage, extirpation of foreign bodies, and washing of lesions with antiseptic solutions) have been indicated in cutaneous or subcutaneous lesions and osteomyelitis. Nevertheless, antimicrobial therapy is effective in ~30% of nocardial mastitis and in pulmonary or extrapulmonary (disseminated) infections in companion and production animals.
Intravenous fluid therapy, oxygen supplementation, and other forms of supportive care may be needed in cases of pulmonary and systemic nocardiosis.
Usually, cutaneous or subcutaneous lesions have a good prognosis; disseminated or pulmonary Nocardia infections have a poor prognosis. High mortality rates observed in pulmonary and disseminated nocardiosis have been attributed to virulence of the strain, site and severity of infection, host immune status, underlying conditions, delayed diagnosis, and improper treatment.
Control and Prevention of Nocardiosis in Animals
There are no specific or effective measures to control or prevent animal and human nocardiosis, probably because of the soilborne nature and wide environmental distribution of the microorganism globally. In companion animals, immunosuppressive pathogens or debilitating conditions should be investigated as predisposing factors.
Particularly with bovine intramammary infections by Nocardia, general recommendations for control and prevention are based on measures for environmental mastitis: early microbiological mastitis diagnosis, proper hygiene at milking, adequate antiseptic concentrations in postdipping and (especially) predipping solutions, high-quality water to wash the udder and the milking equipment, removal of organic material from the milking area, and strict cleanliness during intramammary therapy procedures. Because of the poor success rates in the treatment of bovine and goat mastitis, segregation of infected animals, chemical drying of affected mammary quarters, or culling of animals should be considered to control nocardial mastitis in herds.
Public Health Considerations of Nocardiosis in Animals
Human nocardiosis is typically an opportunistic disease. In some countries, its clinical impact is poorly understood, and it may be underdiagnosed. Reports of human nocardiosis have increased worldwide. Although clinical disease apparently occurs mainly in immunocompromised patients, nocardiosis has been described in immunocompetent humans as well. Historically, species of the former N asteroides complex were the main species described in human nocardiosis. Via the use of molecular methods and rearranged taxonomy, a great number of Nocardia spp have been reported among clinically affected humans, including N cyriacigeorgica, N brasiliensis, N nova, N farcinica, N asiatica, N otitidiscaviarum, N araoensis, N arthritidis, N paucivorans, N beijingensis, N exalbida, N terpenica, N abscessus, N grenadensis, and N ignorata.
Superficial skin infections, lymphocutaneous-subcutaneous lesions, mycetoma, and disseminated infections (affecting the lungs, CNS, kidneys, and joints) are major forms of Nocardia infections in humans, although pulmonary manifestation is the most common. Clinical cases of the disease are strongly associated with immunosuppressive or debilitating disorders, including HIV infection or AIDS, solid organ transplants, pulmonary diseases, cirrhosis, neoplasia, metabolic disorders (eg, diabetes), alcoholism, and rheumatic problems (lymphosarcoma or lymphoma), as well as prolonged use of corticosteroid therapy.
The environment is the natural reservoir of Nocardia for human and animal infections. Most cases of environment to human transmission probably occur by inhalation of the pathogen in dry, warm climate regions (aerosolization). Trauma with skin inoculation is another form of transmission of the bacterium to humans. Several cases of cutaneous or subcutaneous nocardiosis have been reported in humans secondary to bites or scratches from apparently healthy dogs and cats. However, human nocardiosis is not usually transmitted from person to person or by nosocomial infections.
Experimental studies of temperature resistance, using species of the former N asteroides complex and N brasiliensis isolated from bovine milk and submitted to time-temperature conditions used in usual pasteurization procedures, showed relative thermoresistance of Nocardia and the potential risk of pathogen transmission to humans by milk or milk products.
Precautions should be taken among humans who have immune dysfunctions or debilitating diseases, who are living with HIV infection or AIDS, or who are receiving immunosuppressive drug therapy. Especially important is to avoid contact with soil or organic material from environments contaminated by domestic animals, as well as contamination of traumatic cutaneous lesions or close contact with animals suspected of having nocardiosis.
Key Points
Nocardia spp are opportunistic pathogens associated with suppurative to pyogranulomatous infections in animals and humans.
Environmental microflora should be considered in control and preventive approaches.
Mastitis, pneumonia, abscesses, and cutaneous-subcutaneous lesions are the main clinical signs in production and companion animals and usually are refractory to conventional therapy.
For More Information
Also see pet health content regarding immune-deficiency diseases in horses; nocardiosis in dogs and in horses; canine distemper; feline leukemia virus (FeLV); actinomycosis in dogs and in horses; and actinobacillosis in dogs and in horses.
