Cutaneous Nocardiosis

Presentation A 51-year-old man presented to the multidisciplinary wound clinic with right lower-extremity cellulitis and multiple open wounds of 6 months duration (Figure 1). His past medical history was significant for hypertension and insulin-dependent diabetes mellitus. Injured while gardening, his leg initially developed small punctures with surrounding contusions. As local erythema and edema evolved, the wounds became pustules and developed bullae. These chronic, worsening wounds opened and began draining, causing him to seek medical attention. Diagnosis Wound culture results and wound biopsy revealed Nocardia brasiliensis infection with chronic granulomatous tissue consistent with a chronic wound. Discussion Nocardiosis is an infection caused by the bacteria of the order Actinomycetales. They are gram-positive filamentous bacteria. Nocardiosis can be caused by 10 different species of the family, but N. asteroides,^1–5N. brasiliensis,^6,7 and N. caviae are the most common species causing human infection.^8,9Nocardia asteroides accounts for 90% of all nocardial infections.^1–5,10,11 Nocardiosis is typically an opportunistic pulmonary infection that affects immunocompromised individuals. It can become systemic and often forms abscesses in the brain and skin.^1,2,4,5,7 Once disseminated to the brain, N. asteroides has a mortality rate as high as 87%.¹¹Nocardia brasiliensis accounts for 7–10% of all nocardial infections but is the predominate Nocardia infection seen in cutaneous infections.^6,7,10,11Nocardia caviae accounts for only 3% of cases.11 Overall, the rate of nocardial infection is on the rise with approximately 500–1,000 estimated cases each year.^11,12 In 1888, Nocard first described an acid-fast actinomycete that caused a fatal disease in cattle known as bovine farcy.^13,14,15 Three years later, Eppinger reported a man with pleuropulmonary disease, cerebral abscesses, and meningitis caused by the aerobic, gram-positive, acid-fast actinomycete, which he called a “pseudo-tuberculosis.”^14,15,16 Over many years, the organism became known as Nocardia. In 1909, Lindenburg first isolated a separate subspecies, N. brasiliensis, from the leg of a Brazilian man.¹¹Nocardia brasiliensis is the most common cause of primary cutaneous nocardiosis.^6,7,10,11 It is typically associated with traumatic inoculation of contaminated soil. Usually seen in gardeners, it is often associated with thorn puncture wounds, particularly from roses. This sometimes leads to the misdiagnosis of rose gardener’s disease, which is caused by the fungus Sporotrichum schenckii.^10,14,17,18 Unlike N. asteroides, N. brasiliensis is more commonly a disease of the immunocompetent.^6,7,11 This may be due to the fact that N. brasiliensis is the most virulent of the species, according to studies performed by Gonzalez Ochoa.^7,11,19,20 Although the disease can initially present as an ulcer, abscess, granuloma, or cellulitis, it usually presents as pyodermatous lesions, which then form abscesses leaving tender subcutaneous nodules that may open spontaneously to drain.^7,10,11 The abscesses are filled with a thick yellow material called sulfur granule.^11,21 They often spread in a linear fashion under the skin to form separate sinuses.^7,10,22 Less commonly, the disease can involve the lymphatic system and spread directly to the lymph nodes.^6,15,17,18 Eventually, the disease can disseminate and spread to virtually any organ, most commonly the brain. Overall dissemination is far less common with N. brasiliensis when compared to N. asteroides.^6,11,17 Diagnosis can be suggested by the presence of a filamentous, branching, gram-positive organism with Gram stain.^{6,7,10,11,21,23} Another pathogen that has a similar Gram stain appearance is the organism Actinomyces israelii. Unlike its fungal brother, A. israelii, Nocardia are acid-fast stainable using the Ziehl-Neelson method. This is an important distinction, because although these organisms can form sulfur granules in the skin, mimicking each other, treatment differs between the 2 organisms.^11,21,22 Culture identification will definitively diagnose N. brasiliensis. The organism is not particularly difficult to culture but requires longer than normal incubation. It will grow on blood or chocolate agar in an aerobic environment in 2–5 days.^{10,11,22,23,24}Nocardia brasiliensis can be differentiated from the other Nocardia species because it digests casein and tyrosine but not xanthine.⁷ Some antibiotic resistance is possible; therefore, culture susceptibilities are necessary to guide antibiotic choice.²³ Treatment of N. brasiliensis requires long-term antibiotics with surgical drainage and debridement as needed.^11,22,24Nocardia brasiliensis was originally treated with concentrated potassium iodine with moderate success.^6,25 Sulfonamides then became the most commonly used antibiotics to treat these infections.^11,15,17,26 Trimethoprim-sulfamethoxazole (TMP-SMX) is the current antibiotic of choice in treating cutaneous Nocardia infections.^{6,11,12,22,26,27} The duration of therapy is still under debate, but a prolonged course is recommended from 3 months up to 1 year.^12,26,28 Reports of strains resistant to TMP-SMX are rare. Alternative antibiotics include streptomycin, rifampin, and amikacin.^11,27 Disseminated disease may require the combination of streptomycin and TMP-SMX.²⁷Nocardia brasiliensis infections have an overall recovery rate of 89% with treatment. The single most important factor in determining the outcome of the disease is the location of infection. If the infection is confined to the skin and soft tissue, recovery rate reaches 100%. If the primary infection is within the lung, the mortality rate becomes 17%. Once disseminated, the mortality with treatment can be as high as 66%.¹¹ Patient Management The patient was admitted to the hospital for wound care and intravenous penicillin. Initially, the wounds responded to therapy with decreased erythema and edema; localized abscess formation followed. Incision, drainage, and wound debridement were performed on multiple occasions (Figure 2). The wounds extended deep into the soft tissue with subcutaneous tracts interconnecting each abscess. The pockets contained various amounts of purulent material, which was cultured. Identification of N. brasiliensis was made after 72 hours of growth. Subsequent therapy consisted of topical silver sulfadiazene, intravenous (IV) imipenem for 10 days, and oral TMP-SMX. After 6 weeks of treatment, the wounds had healed. Oral TMP-SMX was continued for 6 months. The wounds remained healed at 1-year follow-up (Figure 3). Conclusion Nocardia brasiliensis is a rare cause of chronic wounds that can have deadly consequences without appropriate treatment. It is associated with traumatic inoculation of contaminated soil. Infections can present as cellulitis, ulcers, abscesses, or pustules that become chronic. The presence of sulfur granules and filamentous, gram-positive bacteria can point to this etiology. Final diagnosis is made by standard aerobic culture and sensitivity for a total of 5 days. Appropriate treatment consists of surgical debridement and oral TMP-SMX for an extended period of time. If caught early, cure rates can reach 100%.