Sporothrix schenckii

OVERVIEW: What every clinician needs to know

Pathogen name and classification

• Sporothrix schenckii, a thermally dimorphic fungus, causes sporotrichosis. This fungus grows as a mold in the environment and in the laboratory at 25°C to 28°C. At body temperature and in the laboratory at 35°C to 37°C, the organism grows as a yeast.

What is the best treatment?

• All forms of sporotrichosis require antifungal therapy to eradicate the organism. Itraconazole is preferred for fixed cutaneous, lymphocutaneous, osteoarticular, and less severe pulmonary sporotrichosis. Amphotericin B is needed for disseminated infection, meningitis, and severe pulmonary infection. S. schenckii is resistant to echinocandins and voriconazole, and there is minimal experience using posaconazole for this infection. In some localized cutaneous lesions, local heat therapy can cause the lesions to regress.

• Whenever itraconazole is used, serum concentrations should be measured after 2 weeks of therapy. To ensure adequate absorption, the capsule formulation must be taken with food, and acid-inhibiting agents (proton pump inhibitor or H2 blockers) should be avoided. Itraconazole solution achieves higher serum levels and should be taken on an empty stomach; unfortunately, it is less well tolerated than the capsules. Drug interactions, some of which are life-threatening, are common; all concomitant medications should be carefully reviewed before starting itraconazole.

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• Cutaneous and lymphocutaneous sporotrichosis: oral itraconazole, given as 100 to 200mg daily, is the drug of choice. Although there are data suggesting 100mg is effective for some patients, the expert panel that formulated the Infectious Diseases Society of America guidelines for the management of sporotrichosis felt the data for 200mg daily were more compelling. Therapy should continue for 2 to 4 weeks after the lesions have healed; usually about 3 to 6 months of therapy are given.

  Saturated solution of potassium iodide (SSKI) has been used to treat sporotrichosis for decades and is effective for many patients. However, it is difficult to administer (beginning with 5-10 drops three times a day in milk or juice and increasing weekly to 40-50 drops three times a day. The drug is poorly tolerated, causing nausea, metallic taste, fever, rash, and salivary gland swelling.

  One alternative agent for these forms of sporotrichosis is terbinafine. There is little experience, but a dosage of 500mg twice a day has been shown to be effective in some patients.

  Other alternatives include high-dose (800mg daily) fluconazole, and local hyperthermia using infrared warming devices. Hyperthermia is difficult to for patients to tolerate and requires consistent application for months.

• Osteoarticular sporotrichosis: itraconazole is the therapy of choice for this form of sporotrichosis. This infection is chronic, the diagnosis is often delayed for months, and the patients generally do not have systemic symptoms; thus, amphotericin B is rarely indicated unless the patient fails azole therapy. The dose of itraconazole is 200mg twice a day. Therapy should continue for at least 12 months. The outcome is poor, with loss of joint function the usual outcome. Fluconazole, 800mg daily, can be tried, but generally is ineffective. SSKI and terbinafine are not effective.

• Pulmonary sporotrichosis: if the patient is seriously ill, initial therapy should be amphotericin B and should be given as a lipid formulation at a dosage of 3 to 5mg/kg daily. For those less ill and for step-down therapy after the patient responds to amphotericin B, itraconazole, 200mg twice a day, is recommended. Therapy should continue for at least 12 months. The outcome is poor, in part because of almost universal underlying chronic pulmonary disease (COPD).

• Disseminated sporotrichosis: therapy with amphotericin B is required for this rare form of sporotrichosis. A lipid formulation is preferred at a dose of 3 to 5mg/kg daily. If meningitis is present, the dose should be 5g/kg daily and should be administered for at least 4 to 6 weeks. Step-down therapy is with itraconazole after the patient has shown a response to amphotericin B therapy, and therapy should continue for at least 12 months. For patients who remain immunosuppressed, life-long suppressive therapy with itraconazole is recommended.

• Children with sporotrichosis: children almost always have cutaneous or lymphocutaneus forms of sporotrichosis. They can be treated the same as adults using a dosage of 100mg daily or 6 to 10mg/kg daily of itraconazole, not to exceed 400mg daily. SSKI can also be used, but is often poorly tolerated by children.

• Pregnant women with sporotrichosis: the safest antifungal agent during pregnancy is amphotericin B. Azoles have been linked to birth defects, especially when given in the first trimester, and should be avoided. SSKI causes thyroid toxicity in the fetus and cannot be used. For local cutaneous or lymphocutaneus lesions, waiting until the baby is delivered or perhaps, using local hyperthermia are the best options. For disseminated and other serious disease, amphotericin B can be given during pregnancy without harming the fetus.

How do patients contract this infection, and how do I prevent spread to other patients?

• S. schenckii is found world-wide. The greatest number of cases are reported from South America, North America, and Japan. The organism is found in soil, moss, and decaying wood. Infection follows inoculation of the conidia (spores) of the fungus through the skin by a sharp object, such as a thorn, pine needle, or wood splinter. Not surprisingly, landscapers and gardeners are frequently infected. Outbreaks have occurred in children who were playing in bales of straw, in topiary workers who worked with contaminated plants affixed to chicken wire, and among Christmas tree farmers who received pine seedlings in contaminated moss.

• S. schenckii can be transmitted as a zoonosis, primarily from cats that have active infection, but also from other animal scratches that allow soil to be inoculated (Figure 1). Sporotrichosis is an occupational hazard among veterinarians. A large outbreak linked to infected cats continued for several years in Rio de Janeiro.

• Infection control issues: this organism is not transmitted from person-to-person; isolation precautions are not needed.

Figure 1.

What host factors protect against this infection?

• The host factors important in defense against S. schenckii are primarily neutrophils, monocytes, and macrophages that ingest and kill the yeast phase organisms. Antibodies are not protective.

• The importance of cell-mediated immunity in protecting against S. schenckii was shown when patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) were reported with disseminated infection, an exceedingly uncommon manifestation of sporotrichosis. Murine models have verified the role of cell-mediated immunity in containing the infection.

• Not surprisingly, cytokines, especially tumor necrosis factor, also appear to be important in the host’s ability to contain infection with S. schenckii

• The tissue reaction in the lymphocutaneous form of the infection is a mixed pyogenic and granulomatous response.

What are the clinical manifestations of infection with this organism?

• Lymphocutaneous infection is the most common manifestation of infection with S. schenckii. Most lesions occur on the hands and arms, but can also appear on the lower extremity, trunk, and face. The primary lesion develops within a few weeks at the site of inoculation and usually begins as a small nodule that enlarges and ultimately ulcerates. Most lesions are only mildly painful and are not pruritic. Drainage from the site is minimal and usually serous and without odor. Over the next several weeks, new nodules appear in the distribution of the lymphatic drainage of the primary lesion. The lesions begin as nodules and can remain nodular or ulcerate. In some patients, lymphangitis is obvious. Lymph nodes draining the site of infection can enlarge and become painful (Figure 2, Figure 3).

• Fixed cutaneous infection appears to be more common in South America than in North America. In this form of sporotrichosis, a single lesion develops, often on the face, and does not develop a lymphangitic component (Figure 4). The lesion can wax and wane but will not disappear unless therapy is given. The appearance can be ulcerated or verrucous. Organisms causing this form of sporotrichosis tend to be less thermotolerant than those that cause lymphocutaneous sporotrichosis, growing very poorly at temperatures above 35°C.

• Osteoarticular sporotrichosis is uncommon, and appears to occur more often in those who drink alcohol. Septic arthritis can occur following traumatic inoculation, but most often is a result of hematogenous spread to the joint. Bursitis and tenosynovitis also occur, and the latter can present as carpal tunnel syndrome. Bone involvement is less common and it often occurs adjacent to a joint infected with S. schenckii.

• Pulmonary sporotrichosis is generally a subacute to chronic infection. It occurs almost entirely in patients who have underlying COPD and is thought to be initiated with inhalation of the conidia of S. schenckii. The symptoms are fever, fatigue, weight loss, cough, sputum production, and hemoptysis. Chest radiographs show upper lobe cavitary infiltrates. Patients are often thought to have chronic cavitary pulmonary histoplasmosis, tuberculosis, or an atypical mycobacterial infection.

• Disseminated sporotrichosis is rare, occurring almost entirely in patients who have cellular immune deficiencies, most commonly HIV infection. Dissemination may present primarily as multiple cutaneous lesions, clearly spread by the hematogenous route, or as widespread visceral involvement, including meningitis. Rarely, patients may present with isolated chronic meningitis, similar to the presentation of cryptococcal meningitis.

Figure 2.

Figure 3.

Figure 4.

What common complications are associated with infection with this pathogen?

• Few complications occur with localized infection. The lesions often heal without scarring. However, if not treated, the lesions can persist for years.

• Related, in part, to underlying COPD, pulmonary sporotrichosis can lead to progressive lung dysfunction, and the mortality rate is high.

• Osteoarticular sporotrichosis is associated with joint destruction and with scarring when tendons are involved.

• Disseminated infection is associated with a high mortality rate.

How should I identify the organism?

• S. schenckii is a thermally dimorphic fungus, meaning that it grows as a mold in the environment and at 25°C to 28°C in the laboratory and as a yeast in tissues and at 35°C to 37°C in the laboratory.

• Diagnosis is made by biopsy of a skin lesion in most cases. Sputum and synovial fluid should be cultured in pulmonary and articular sporotrichosis, respectively. Blood cultures are sometimes positive in disseminated infection, and cerebrospinal fluid should be cultured in meningeal infection.

• In tissues, the yeast forms are small (4-6μm) oval or round budding yeasts that are best stained with methenamine silver stain. However, the yeasts are often difficult to see in tissues, and culture is more sensitive.

• S. schenckii usually grows within 1 to 2 weeks on Sabouraud dextrose agar at room temperature as an off-white mold that darkens with time. It forms thin, septate, branching hyphae with conidia (spores) attached in a bouquet-like fashion. Identification requires transforming the mold to the yeast phase at 37°C in the laboratory, and most clinical laboratories have to send the culture to a reference laboratory to identify the organism as S. schenckii.

• There is no commercially available polymerase chain reaction assay.

• Serology is not useful for diagnosis.

How does this organism cause disease?

• The virulence factors of S. schenckii have not been well characterized. It is not considered a highly virulent organism, causing mostly localized cutaneous infection.

• The best characterized virulence factor is thermotolerance. Those strains that can grow at 37°C are the ones that are able to cause lymphangitic spread and visceral involvement in humans and in animal models. Conversely, those strains that lack this tolerance to higher temperatures generally cause fixed cutaneous lesions in humans and cannot spread to cause disseminated infection in animal models.

• Other virulence factors include extracellular proteinases and melanin, a common virulence factor for many fungi, but the exact role of these factors has not been elucidated.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Kauffman, CA, Bustamante, B, Chapman, SW, Pappas, PG. “Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 45. 2007. pp. 1255-65. (This guideline was developed by reviewing the available literature on sporotrichosis and focusing on treatment aspects. The specific recommendations are graded by strength of evidence and by quality of evidence. The guideline notes that few randomized controlled treatment trials have been performed for this disease, and the recommendations for the uncommon forms of sporotrichosis are based on expert opinion and clinical experience.)

Bustamante, B, Lama, J, Mosquera, C. “Sporotrichosis in human immunodeficiency virus infected Peruvian patients. Two case reports and literature review”. Infect Dis Clin Pract. vol. 17. 2009. pp. 78-83. (Most up-to-date review of the manifestations of sporotrichosis in patients who have HIV infection.)

Barros, MD, de Almeida Paes, R, Schubach, AO. “and sporotrichosis”. Clin Microbiol Rev. vol. 24. 2011. pp. 633-54. (Excellent review of sporotrichosis with an emphasis on the epidemiological and clinical findings from the extensive epidemic of sporotrichosis in Rio de Janeiro that involves transmission from cats.)

Hajjeh, R, McDonnell, S, Reef, S. “Outbreak of sporotrichosis among tree nursery workers”. J Infect Dis. vol. 174. 1997. pp. 499-504. (Well-described outbreak of lymphocutaneous sporotrichosis among workers who were creating topiary sculptures on wire frames using ivy plants packaged in contaminated moss.)

Sharkey-Mathis, PK, Kauffman, CA, Graybill, JR. “Treatment of sporotrichosis with itraconazole. NIAID Mycoses Study Group”. Am J Med. vol. 95. 1993. pp. 279-85. (Early study from the Mycoses Study Group showing the efficacy of itraconazole for various forms of sporotrichosis.)

de Lima Barros, MD, Schubach, AO, da Vasconcellos Carvalhaes de Oliveira, R. “Treatment of cutaneous sporotrichosis with itraconazole. study of 645 patients”. Clin Infect Dis. vol. 52. 2011. pp. e200-6. (Largest series of cases of sporotrichosis treated with itraconazole; patients are those associated with the large cat-associated outbreak of sporotrichosis in Rio de Janeiro.)

Kauffman, CA, Pappas, PG, McKinsey, DS. “Treatment of lymphocutaneous and visceral sporotrichosis with fluconazole”. Clin Infect Dis. vol. 22. 1996. pp. 46-50. (Mycoses Study Group study showing poor response of sporotrichosis to fluconazole.)

Chapman, SW, Pappas, PG, Kauffman, CA. “Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 mg and 1000 mg daily) in the treatment of cutaneous or lymphocutaneous sporotrichosis”. Mycoses. vol. 47. 2003. pp. 62-8. (One of the few randomized, blinded, controlled clinical trials for treatment of sporotrichosis, showing the effectiveness of the larger dose of terbinafine for localized sporotrichosis.)

Cabezas, C, Bustamante, B, Holgado, W. “Treatment of cutaneous sporotrichosis with once daily dose of postassium iodide”. Pediatr Infect Dis J. vol. 15. 1996. pp. 352-4. (Treatment trial exploring more effective ways to ensure compliance with potassium iodide therapy in children with sporotrichosis.)

Hiruma, M, Kawaga, S. “The effects of heat on and “. Mycopathologia. vol. 84. 1998. pp. 21-30. (This paper explains the rationale for using hyperthermia to treat sporotrichosis and comments on the types of devices that can be used.)

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