Introduction
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. HIV infection, chronic lung disease, and chronic use of immunosuppressant medications appear to be the 3 most common underlying risk factors for disseminated nocardiosis.1
Red nodules on a patient with disseminated nocardiosis.
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.
Ulcer on the arm of a patient with primary cutaneous nocardiosis.
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.2 Neutrophilic eccrine hidradenitis is more commonly seen with the use of chemotherapeutic agents.
Also see Nocardiosis (infectious disease focus) and Nocardiosis (pediatrics focus).
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.3 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.4
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.5
Clinical
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.6 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.7 A case report revealed Nocardia species as the causative organisms in a patient receiving infliximab and prednisone. Inquire about compliance with prophylactic antibiotics with certain underlying conditions, including HIV infection and certain cancers, including leukemia.
- Given the sensitivity of Nocardia species to trimethoprim-sulfamethoxazole (TMP-SMZ), compliance with prophylaxis greatly decreases the likelihood of nocardiosis in these patients.8
- 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 Wallace9 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).10
- 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 laser in situ keratomileusis (LASIK) surgery.11
- 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.12
- 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 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. One review revealed that N paucivorans has a relatively high incidence (>30%) of dissemination.13
More on Nocardiosis |
 Overview: Nocardiosis |
| Differential Diagnoses & Workup: Nocardiosis |
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References
Minero MV, Marin M, Cercenado E, Rabadan PM, Bouza E, Munoz P. Nocardiosis at the turn of the century. Medicine (Baltimore). Jul 2009;88(4):250-61. [Medline].
Antonovich DD, Berke A, Grant-Kels JM, Fung M. Infectious eccrine hidradenitis caused by Nocardia. J Am Acad Dermatol. Feb 2004;50(2):315-8. [Medline].
Beaman BL, Burnside J, Edwards B, Causey W. Nocardial infections in the United States, 1972-1974. J Infect Dis. Sep 1976;134(3):286-9. [Medline].
Berd D. Nocardia brasiliensis infection in the United States: a report of nine cases and a review of the literature. Am J Clin Pathol. Aug 1973;60(2):254-8. [Medline].
Law BJ, Marks MI. Pediatric nocardiosis. Pediatrics. Oct 1982;70(4):560-5. [Medline].
Gyotoku T, Kayashima K, Nishimoto K, Ono T. Cutaneous nocardiosis developing around gravel inserted during a traffic injury. J Dermatol. Dec 2002;29(12):803-9. [Medline].
Singh SM, Rau NV, Cohen LB, Harris H. Cutaneous nocardiosis complicating management of Crohn's disease with infliximab and prednisone. CMAJ. Oct 26 2004;171(9):1063-4. [Medline].
Bernoux D, Mialou V, Rodríguez-Nava V, et al. [Disseminated nocardiosis in a child with acute lymphoblastic leukemia]. Arch Pediatr. Mar 2008;15(3):275-8. [Medline].
Satterwhite TK, Wallace RJ Jr. Primary cutaneous nocardiosis. JAMA. Jul 27 1979;242(4):333-6. [Medline].
Kostman JR, DiNubile MJ. Nodular lymphangitis: a distinctive but often unrecognized syndrome. Ann Intern Med. Jun 1 1993;118(11):883-8. [Medline].
Garg P, Sharma S, Vemuganti GK, Ramamurthy B. A cluster of Nocardia keratitis after LASIK. J Refract Surg. Mar 2007;23(3):309-12. [Medline].
Clark NM, Braun DK, Pasternak A, Chenoweth CE. Primary cutaneous Nocardia otitidiscaviarum infection: case report and review. Clin Infect Dis. May 1995;20(5):1266-70. [Medline].
Gray TJ, Serisier DJ, Gilpin CM, Coulter C, Bowler SJ, McCormack JG. Nocardia paucivorans--a cause of disseminated nocardiosis. J Infect. Feb 2007;54(2):e95-8. [Medline].
Smego RA Jr, Castiglia M, Asperilla MO. Lymphocutaneous syndrome. A review of non-sporothrix causes. Medicine (Baltimore). Jan 1999;78(1):38-63. [Medline].
Lewis KE, Ebden P, Wooster SL, Rees J, Harrison GA. Multi-system Infection with Nocardia farcinica-therapy with linezolid and minocycline. J Infect. Apr 2003;46(3):199-202. [Medline].
Brown-Elliott BA, Ward SC, Crist CJ, Mann LB, Wilson RW, Wallace RJ Jr. In vitro activities of linezolid against multiple Nocardia species. Antimicrob Agents Chemother. Apr 2001;45(4):1295-7. [Medline].
Fukuda H, Saotome A, Usami N, Urushibata O, Mukai H. Lymphocutaneous type of nocardiosis caused by Nocardia brasiliensis: a case report and review of primary cutaneous nocardiosis caused by N. brasiliensis reported in Japan. J Dermatol. Jun 2008;35(6):346-53. [Medline].
Curry WA. Human nocardiosis. A clinical review with selected case reports. Arch Intern Med. Jun 1980;140(6):818-26. [Medline].
Hay RJ. Nocardial infection of the skin. J Hyg (Lond). Dec 1983;91(3):385-91. [Medline].
Kalb RE, Kaplan MH, Grossman ME. Cutaneous nocardiosis. Case reports and review. J Am Acad Dermatol. Jul 1985;13(1):125-33. [Medline].
Lerner PI. Nocardiosis. Clin Infect Dis. Jun 1996;22(6):891-903; quiz 904-5. [Medline].
Mahgoub ES. Agents of mycetoma. In: Mandell et al, eds. Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone; 1995:2327.
Maraki S, Chochlidakis S, Nioti E, Tselentis Y. Primary lymphocutaneous nocardiosis in an immunocompetent patient. Ann Clin Microbiol Antimicrob. Nov 15 2004;3:24. [Medline].
McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol Rev. Jul 1994;7(3):357-417. [Medline].
Moeller CA, Burton CS 3rd. Primary lymphocutaneous Nocardia brasiliensis infection. Arch Dermatol. Oct 1986;122(10):1180-2. [Medline].
Naka W, Miyakawa S, Niizeki H, Fukuda T, Mikami Y, Nishikawa T. Unusually located lymphocutaneous nocardiosis caused by Nocardia brasiliensis. Br J Dermatol. Apr 1995;132(4):609-13. [Medline].
Nishimoto K, Ohno M. Subcutaneous abscesses caused by Nocardia brasiliensis complicated by malignant lymphoma. A survey of cutaneous nocardiosis reported in Japan. Int J Dermatol. Sep 1985;24(7):437-40. [Medline].
Palmer DL, Harvey RL, Wheeler JK. Diagnostic and therapeutic considerations in Nocardia asteroides infection. Medicine (Baltimore). Sep 1974;53(5):391-401. [Medline].
Robboy SJ, Vickery AL Jr. Tinctorial and morphologic properties distinguishing actinomycosis and nocardiosis. N Engl J Med. Mar 12 1970;282(11):593-6. [Medline].
Schiff TA, McNeil MM, Brown JM. Cutaneous Nocardia farcinica infection in a nonimmunocompromised patient: case report and review. Clin Infect Dis. Jun 1993;16(6):756-60. [Medline].
Tsuboi R, Takamori K, Ogawa H, Mikami Y, Arai T. Lymphocutaneous nocardiosis caused by Nocardia asteroides. Case report and literature review. Arch Dermatol. Oct 1986;122(10):1183-5. [Medline].
Wallace RJ Jr, Tsukamura M, Brown BA, et al. Cefotaxime-resistant Nocardia asteroides strains are isolates of the controversial species Nocardia farcinica. J Clin Microbiol. Dec 1990;28(12):2726-32. [Medline].
Ye Z, Shimomura H, Kudo S, Arao T, Sato Y, Ono T. A case of lymphocutaneous nocardiosis with a review of lymphocutaneous nocardiosis reported in Japan. J Dermatol. Feb 1996;23(2):120-4. [Medline].
Zecler E, Gilboa Y, Elkina L, Atlan G, Sompolinsky D. Lymphocutaneous nocardiosis due to nocardia brasiliensis. Arch Dermatol. May 1977;113(5):642-3. [Medline].
Further Reading
Keywords
nocardiosis, nocardial infection, systemic nocardial disease, mycetoma, maduromycosis, Madura foot, soil-borne infection, soil infection, gardening injury
