AUTHOR AND EDITOR INFORMATION

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• Follow-up
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Nocardiosis is an infection caused by several species of soil-borne aerobic bacteria belonging to the genus Nocardia. Similar to anaerobic organisms of the genus Actinomyces, Nocardia species often form thin filaments that can resemble but are much thinner than those of true fungi (1-2 µm vs 3-5 µm in diameter).

Nocardiosis can be divided into 2 broad categories, disseminated and cutaneous.

Disseminated nocardiosis

Disseminated nocardiosis is responsible for most occurrences of nocardiosis, is most commonly caused by Nocardia asteroides, and typically affects immunocompromised hosts, although individuals with presumed immunocompetency also can develop the disease.

Primary cutaneous nocardiosis

Primary cutaneous nocardiosis, most commonly caused by Nocardia brasiliensis, typically affects immunocompetent individuals with a history of trauma and can be subdivided into 3 clinical entities that include (1) lymphocutaneous infection, (2) mycetoma, and (3) superficial skin infection, including ulceration, abscess, and cellulitis. Involvement of the skin can occur as a result of secondary dissemination from systemic infection. Cutaneous involvement with N asteroides is usually secondary to hematogenous dissemination from a pulmonary focus. Dissemination to the skin is estimated to occur in approximately 10% of patients with systemic nocardial infection, second in incidence only to CNS involvement.

Lymphocutaneous nocardiosis

Lymphocutaneous nocardiosis is rare and often misdiagnosed as sporotrichosis (more common) because it also manifests as a primary lesion at the site of injury, followed by a proximal spread of lymphangitis and nodular lesions along the lymphatics. The lymphocutaneous or sporotrichoid form is the least common form of primary cutaneous nocardiosis. However, it probably is more common than reported, and diagnosis requires a high index of suspicion. Of 14 patients reported from 1920-1986, more than half had a history of gardening or thorn injuries.

Mycetoma

Mycetoma, also termed maduromycosis or Madura foot, is named after the Indian region where it was first described. Mycetoma is a chronic, deep, progressively destructive, and deforming infection of skin, subcutaneous tissues, fascia, bone, and muscle following localized trauma. The disorder occurs most commonly on the extremities, especially the foot. Mycetoma manifests as a tumorlike area of localized edema or massive enlargement, with erythema and multiple draining sinus tracts. Often, mycetoma is described as a triad of tumefaction, sinus tract formation, and grains (sulfur granules).

Approximately half the mycetoma occurrences are caused by Nocardia species. In Mexico and Central and South America, N brasiliensis is the agent involved in 90% of mycetomas.

Mycetoma caused by filamentous bacteria is termed actinomycetoma. Actinomycetoma can be caused by N brasiliensis, N asteroides, Nocardia madurae, Streptomyces somaliensis, Streptomyces pelletieri, and Actinomyces israelii.

Mycetoma caused by true fungi is termed eumycetoma. Eumycetoma can be caused by Pseudallescheria boydii, Phialophora jeanselmei, Madurella mycetomi, Madurella grisea, Cephalosporium falciforme, and Cephalosporium recifei.

In the United States, mycetoma is rare and is more commonly caused by P boydii than nocardial or other organisms. Histologically, mycetoma is often granulomatous and fibrosing and is the only clinical form of nocardiosis regularly associated with sulfur granules.

Superficial skin infection

The remaining primary skin infections of nocardiosis manifest as pustules, abscesses, or cellulitis and often mimic disease caused by more common organisms, such as Staphylococcus species. Nocardiosis probably causes superficial skin infections much more commonly than reported. The reason for this is 2-fold. First, most of these infections are treated empirically, and cultures often are not performed. If the infection clears, it is assumed it to have been of staphylococcal or streptococcal origin. Second, Nocardia is a slow-growing bacterium that rarely appears in culture prior to 48 hours. If no growth is seen within 48 hours, cultures are often discarded, and no definitive diagnosis is made.

One case report of infectious neutrophilic eccrine hidradenitis has been attributed to nocardiosis. Neutrophilic eccrine hidradenitis is more commonly seen with the use of chemotherapeutic agents.

Pathophysiology

Virulent strains of Nocardia species are often facultative intracellular pathogens that successfully evade the host's immune response by resisting phagocytosis, inhibiting phagosome-lysosome fusion, and resisting the oxidative killing mechanism of phagocytes. Cell-mediated immunity, triggered by activated macrophages and the induction of lymphocyte-mediated killing of Nocardia organisms, is the body's primary defense against these pathogens.

Pulmonary disease is the most common manifestation of nocardial infection. Dissemination has been found in almost every organ, most commonly in the brain and skin. Nocardiosis commonly results in multisystemic illness, particularly in immunocompromised patients.

Frequency

United States

According to the Infectious Disease Society of America, 500-1000 patients with nocardiosis present annually. Many sources report that skin is primarily involved in 5-7% of these infections. Most experts believe this figure is underestimated because many nocardiosis infections mimic more common diseases and are treated with drainage and antibiotics, without identification of the causative organism. Superficial skin infection, including abscess and cellulitis, is the most common subtype of nocardiosis in the United States. Currently, mycetoma is relatively rare in the United States. Most patients with clinical cases caused by N brasiliensis have been seen in the south and southwestern United States.

International

Rates of nocardiosis vary by country. For example, in Japan, 45 patients with cutaneous nocardiosis were reported by 1985. Approximately 90% of those patients had mycetoma. Worldwide, mycetoma is the most common cutaneous manifestation of N brasiliensis infection and is described most often in Mexican and South American field workers.

Mortality/Morbidity

Most cutaneous nocardiosis infections resolve without significant mortality; however, secondary hematogenous dissemination with subsequent mortality has been reported. Morbidity is most significant with the chronic mycetomal form, which may persist for years and may be incurable. The lymphocutaneous type usually responds well to antibiotic therapy within 2-3 months, and superficial skin infections often resolve with empiric antibiotics.

Race

Nocardiosis is primarily related to geographic distribution rather than ethnicity and is more common in Mexican and South American populations.

Sex

The male-to-female ratio is 3:1 in all forms of nocardiosis. The predominance of men performing outdoor labor, rather than an inherent predisposition, may be responsible for this ratio. The lymphocutaneous or sporotrichoid form has a greater than 80% male predominance.

Age

Primary cutaneous nocardiosis may occur in persons from any age group but is more common in middle-aged adults, especially men. Cervicofacial nocardiosis is a subgroup of the lymphocutaneous type that affects children and is clinically distinguishable because it occurs in children, manifesting as facial pustules or papules with associated cervical or submandibular lymphadenopathy and fever without a history of trauma.

CLINICAL

Section 3 of 11  

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History

• Trauma: Elucidating a history of trauma, especially a puncture wound while gardening or a cat's scratch, can help make the correct diagnosis. Vehicular accidents are predisposing factors, particularly if significant exposure to soil occurred. Trauma may have occurred several days to several months prior to clinical illness.


• Occupational exposure: Rural laborers exposed to traumatic injuries while walking barefoot are at highest risk of mycetoma formation. Others at increased risk are farmers and gardeners.


• Immunodeficiency: Immunosuppression is commonly a contributing factor in N asteroides infections but typically is not necessary for infections caused by N brasiliensis. N asteroides is primarily an opportunistic pathogen, while N brasiliensis causes skin infections in healthy hosts. Additionally, with the advent of new immune-response modifying medications (eg, infliximab) for relatively common diseases such as rheumatoid arthritis, Crohn disease, and psoriasis, opportunistic nocardiosis may increase in prevalence. A recent case report revealed Nocardia species as the causative organisms in a patient receiving infliximab and prednisone.


• Resistance to previous antibiotic therapy: Because many nocardial infections mimic infections caused by skin florae, standard antibiotic regimens for staphylococcal and streptococcal species often fail and the infection worsens while the patient is on empiric therapy.


• History of fever: Fever is more common in patients with acute cellulitis and abscess.


• Mild weight loss: Weight loss is more common in patients with the chronic mycetoma variant.


• History of local recurrence: Cellulitis and abscesses caused by nocardial species require prolonged antibiotic therapy or they commonly recur.

Physical

• Superficial skin infection (eg, cellulitis, abscesses, ulcers) - Cannot be distinguished clinically from more common bacterial etiologies
• • Typically, no lymphadenopathy is noted.
  • Fever is common.
  • Superficial skin infection is often accompanied by a pyoderma, which is a purulent crusting lesion that heals with ulcer formation. In 1979, Satterwhite and Wallace¹ reported that 3 of 7 patients had associated pyoderma.
  • Patients may have other less common superficial infections, including paronychia, posttraumatic keratitis and endophthalmitis, and wound infections secondary to compound fractures or sternotomy.


• Lymphocutaneous infection
• • This manifests as an initial ulcerative papule or nodule at the inoculation site with secondary subcutaneous nodules along lymphatic vessels (chaining nodular lymphangitis).
  • It most commonly involves the upper extremities.
  • The lymphocutaneous infection is more acute and inflammatory, with more painful, tender, erythematous lesions, than in infections caused by Sporothrix schenckii.
  • Purulent drainage is noted.
  • Macroscopic sulfur granules can be expressed from lesions, although this is a rare occurrence.
  • Regional lymphadenopathy is common.


• Mycetoma
• • This typically involves the dorsal foot, and it can be localized to the leg, arm, or hand.
  • It is a progressively destructive infection of the skin and can extend to subcutaneous tissues, fascia, bone, and muscle.
  • It appears as an area of localized tumorlike swelling with multiple sinus tracts; however, amazingly, it usually is not painful.
  • Macroscopic sulfur granules commonly can be expressed from sinus tracts.

Causes

• N brasiliensis is responsible for less than 10% of nocardiosis infections but causes most primary cutaneous lesions, especially in superficial skin and lymphocutaneous infections.
• N asteroides is the primary culprit in systemic and pulmonary infections but less often causes cutaneous nocardiosis. Two exceptions include disseminated cutaneous disease, which typically is caused by N asteroides, and mycetoma (in some countries).  Recently, N asteroides has been implicated in ocular infections after LASIK surgery.²
• Nocardia otitidiscaviarum (Nocardia caviae) is an infrequent cause of infection in humans and is believed to be less pathogenic than the more common species of Nocardia. N otitidiscaviarum can cause all 3 subtypes of primary cutaneous nocardiosis. Prior to 1995, of the 28 patients with cutaneous N otitidiscaviarum infections reported in the literature, 16 had superficial skin infections including abscess, ulcers, and wound infections. Mycetomas were classified in 8, and 1 had lymphocutaneous syndrome. Three patients were not classified. N otitidiscaviarum is often resistant to sulfonamides.
• Nocardia farcinica is significant historically because Edmond Nocard first described this species as the cause of bovine farcy in 1888. Clinically, this species is significant to humans because it has a high degree of antibiotic resistance, especially to third-generation cephalosporins and tobramycin. Fortunately, it usually is susceptible to trimethoprim-sulfamethoxazole (TMP-SMZ) and rarely infects humans. Only recently has it been accepted as an important human pathogen. Prior to 1993, N farcinica infection had been reported in 14 patients. The lungs were involved in 7 patients, the brain in 4, and the skin in only 3 patients. Wallace et al have suggested that a significant percentage of drug-resistant N asteroides species actually are N farcinica. Controversy surrounds the identity of N farcinica, either as a truly distinct species or as a variant of N asteroides.
• Nocardia nova, like N farcinica, is a member of the N asteroides complex and is differentiated by its unique antibiotic susceptibility pattern.
• Nocardia transvalensis causes mycetoma in Africa and life-threatening invasive infections in severely immunocompromised persons.
• Nocardia paucivorans is a cause of disseminated nocardiosis in both immunocompromised and immunocompetent persons. A recent review³ revealed that N paucivorans has a relatively high incidence (>30%) of dissemination.

DIFFERENTIALS

Section 4 of 11  

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• Clinical
• Differentials
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Other Problems to be Considered

Superficial skin infection: Streptococcal and staphylococcal infections are more common than nocardial infections. Maintain a high index of suspicion to diagnose infections with nocardial etiology. Notify the laboratory in advance when nocardiosis is suspected so that cultures are grown for longer than 48 hours.

Lymphocutaneous syndrome: S schenckii is the most common cause. A dimorphic fungus causes sporotrichosis infection, and appropriate therapy includes excision, itraconazole, potassium iodide, or amphotericin B. When sophisticated culture techniques are unavailable, nocardiosis and sporotrichosis may be differentiated based on treatment response (nocardial lymphocutaneous syndrome also can be treated effectively with potassium iodide). Sporotrichosis typically follows a more indolent course and has a less inflammatory response compared with nocardiosis, although it also can be purulent.

Other less common causes of lymphocutaneous disease: These may be caused by non-Sporothrix fungi, such as Blastomyces, Coccidioides, Histoplasma, and Cryptococcus; bacteria, such as Francisella tularensis (tularemia), Staphylococcus aureus, and Streptococcus pyogenes; and viruses, such as herpes simplex and cowpox virus.

Mycobacterium marinum and other atypical mycobacteria: Along with Nocardia, M marinum is the most frequent cause of non-Sporothrix lymphocutaneous syndrome in the United States. Recent exposure to fresh- or salt-water sources (eg, fish tanks) provides an important historic clue. Treatment includes minocycline, TMP-SMZ, and rifampin and ethambutol.

Leishmania brasiliensis: Infection is rare in the United States, but it is a relatively common cause of lymphocutaneous syndrome in the Middle East, Africa, Asia, and Latin America.

Mycetoma: The clinical presentation of mycetoma is distinctive. Determine the causative organism because treatment varies according to the infectious agent.

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• Culture: Nocardia species grow in most routine bacterial cultures. Maintain cultures for more than 48 hours because of the slow-growing nature of Nocardia compared with most other bacteria. Submit multiple clinical specimens for culture because smears and cultures are simultaneously positive in only one third of infections. Fungal and acid-fast bacillus cultures may help identify infection by other organisms that can resemble nocardial infection.
• CBC count: Peripheral leukocytosis often is present in acute forms of cutaneous nocardiosis and in systemic disease. Mild anemia can be found with chronic mycetomas.

Imaging Studies

• Perform chest radiography if dissemination from a pulmonary lesion is possible.
• Imaging studies typically are not necessary when a history of traumatic inoculation can be elicited. Local radiographs (eg, foot), CT scans, or MRIs may help in patients with deep infection (eg, mycetoma).

Histologic Findings

• Skin biopsy: Biopsy often reveals a dense mixed inflammatory infiltrate with suppuration (neutrophils prominent), granulation tissue, fibrosis, and granuloma formation.
• Gram stain: Prepare Gram stains from smears of draining areas, touch preparations of tissue, or sections of tissue. Nocardial organisms are thin, delicate, weak-to-strongly gram-positive organisms, and often form filaments. They often are stained irregularly or as beaded branching organisms, usually surrounded by many neutrophils. In cases reported by Satterwhite and Wallace¹, 3 (50%) of 6 revealed gram-positive organisms and 100% revealed many neutrophils.
• Modified Kinyoun acid-fast stain: Nocardia species are weakly acid fast compared with the more strongly acid-fast Mycobacteria, decolorizing with a weak acid (1-2% sulfuric acid instead of acid alcohol).
• Sulfur granules (grains) examination: The size, shape, and color of the grains can help determine the causative agent in mycetoma. Grains can vary from 0.2-5 mm. White-to-yellow grains are usually seen in association with Nocardia, Actinomyces, Streptomyces somaliensis, P boydii, and Cephalosporium. Brown-to-black grains are seen only in association with true dematiaceous fungi, such as Madurella and P jeanselmei. Red grains are seen in association with Streptomyces pelletieri.
  
  
  • Sulfur granules are commonly seen in mycetomas but are seldom found in other cutaneous forms of nocardiosis. These granules appear to be a unique feature of primary cutaneous nocardiosis and are rarely noted with involvement of the lungs, brain, or other viscera.
  • Sulfur granules caused by bacteria tend to contain filaments only 1-2 µm thick, while those caused by fungi have filaments that are 3-5 µm thick. Occasionally, filaments are seen more easily radiating outside of the granule.
• Hematoxylin and eosin stain: Nocardia organisms are not demonstrated with routine hematoxylin and eosin stain and may be seen only after a careful search of sections stained with Gram, Gomori methenamine silver, or acid-fast bacillus stain.

TREATMENT

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Medical Care

Most patients with primary cutaneous nocardiosis require antibiotic therapy to resolve the infection. Recommendations regarding the duration of therapy range from 2-3 months for most cutaneous infections to 1 year for chronic cutaneous and systemic infections. TMP-SMZ is used most frequently for nocardiosis.

Surgical Care

Surgical debridement or excision often is vital in the treatment of nocardiosis. Surgery is most helpful in abscesses and mycetomas, but it can also help resolve lymphocutaneous infection. In a review of nocardial lymphocutaneous syndrome published in 1999⁴, of 50 patients, 11 required surgery as a primary or secondary treatment.

Consultations

• Consult a dermatologist regarding the diagnostic workup and optimization of therapy.
• Consult an infectious disease specialist regarding the diagnostic workup and optimization of therapy.
• Consultation with a general surgeon or orthopedic surgeon may be required if extensive surgical debridement is necessary.

Activity

Activity depends on the severity of illness and the location of the infection.

MEDICATION

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Sulfonamides have been the antimicrobial agents of choice for more than 50 years and are recommended based on accumulated clinical experience because results from in vitro studies have been less than impressive. TMP-SMZ is used most commonly. Other sulfonamides used include (1) sulfadiazine, which is not recommended as first-line therapy because of significant risk of oliguria, azotemia, and crystalluria in patients who do not maintain a high fluid intake, and (2) sulfisoxazole, which is as equally effective as sulfadiazine and much less likely to cause oliguria, although no parenteral form is available (2 g PO q6h in adults).

Potassium iodide is an older therapy active against lymphocutaneous nocardiosis and is not recommended for severe infections or systemic disease.

Newer antimicrobials such as linezolid have been used successfully in combination with more traditional agents in more resistant or severe cases of nocardiosis.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and cover all likely pathogens in the clinical setting. Imipenem is consistently active in vitro, although 18-36% of N farcinica strains are not susceptible and 70% of N brasiliensis strains are resistant. Because most primary cutaneous nocardiosis is caused by N brasiliensis, imipenem is mostly used to treat systemic disease. The parenteral drug of choice for initial therapy in persons with systemic disease is amikacin in combination with imipenem. Tobramycin is an aminoglycoside to which many nocardial strains are resistant, especially N farcinica.

FOLLOW-UP

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Further Outpatient Care

• Close outpatient follow-up care is vital to the success of therapy for cutaneous nocardiosis. Because of the long duration of therapy, relapse is possible. Although the optimal duration of therapy is uncertain, suggestions range from 6 weeks (in minor infections) to 1 year (severe systemic disease).
• Frequent outpatient visits for the first 6 weeks are recommended, followed by less frequent visits if the patient does well clinically.

In/Out Patient Meds

• Antibiotic therapy and appropriate surgical drainage are treatments of choice (see Medication).
• If parenteral therapy is necessary, it need not be continued beyond a period of 3-6 weeks, even in patients with life-threatening systemic disease. With improving clinical status, most patients can be switched safely to oral medications, especially TMP-SMZ.
• Outpatient antibiotics are much more easily administered in oral form, and oral antibiotics have been shown to be just as effective as intravenous forms in patients with cutaneous disease.

Complications

• Recurrence of disease is the most frequent complication. A full course of appropriate antibiotics is essential for preventing recurrence.
• At least 3 cases of dissemination of primary cutaneous nocardiosis have been reported. Despite the rarity of this occurrence, dissemination is associated with a much higher mortality rate.
• If a patient remains ill or febrile despite seemingly adequate therapy, treatment failure may be a result of a sequestered abscess that requires drainage. Often, localization and drainage subsequently result in efficacious results.
• Mycetoma, although rare in developed countries, is much more invasive and destructive than other forms of cutaneous nocardiosis. Because fascia, bone, and muscle are frequently involved in severe untreated mycetoma, wide debridement and amputation are known complications.

Prognosis

• With proper antibiotic selection and course of treatment, the prognosis for patients with primary cutaneous nocardiosis is excellent.
• In disseminated disease in immunocompromised patients, the cure or improvement rate can be as high as 90% with appropriate antibiotic therapy.
• In a review of 137 cases of nocardiosis treated with TMP-SMZ, the cure or improvement rate was as high as 97% for soft tissue infections and as low as 50% with serious CNS infections. Immune suppression significantly affected the cure rate.
• In an immunocompetent host, primary cutaneous nocardiosis is rarely fatal; full recovery can be expected with appropriate therapy.

Patient Education

• Patient education regarding proper wound care is important.
• Patients must be educated about the importance of an extended course of antibiotics, which may be difficult to maintain if the apparent infection has resolved and the patient no longer feels ill.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to identify the organism: Nocardial infections are unusual and often are not recognized. Incubate routine bacterial cultures longer than usual to grow the organism. Some nocardial infections may resemble the more common staphylococcal infections, and those may be treated empirically without cultures.
• Failure to drain abscesses and deep infections (eg, mycetoma): Often these must be drained or incised or the antibiotics may not properly penetrate infected areas.
• Failure to recognize disseminated infection: Nocardiosis can be a localized or disseminated process. Avoid the pitfall of assuming that an infection is localized to the skin or soft tissues.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Red nodules on a patient with disseminated nocardiosis.
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Media file 2:  Ulcer on the arm of a patient with primary cutaneous nocardiosis.
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Media file 3:  Gomori methenamine silver stain demonstrating black filamentous Nocardia species.
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Jun 6, 2007