Treatment of sporotrichosis

INTRODUCTION — Sporotrichosis is a subacute to chronic infection caused by the dimorphic fungus Sporothrix schenckii. Infection usually involves cutaneous and subcutaneous tissues but can occasionally occur in other sites, primarily in immunocompromised patients. Activities associated with the development of sporotrichosis include landscaping, rose gardening, and other activities that involve inoculation of soil through the skin.

Treatment of sporotrichosis varies with the type of disease [1]. Since most manifestations are subacute to chronic and localized, oral antifungal agents are usually preferred. The agent of choice is itraconazole [2]. The rare cases of life-threatening, visceral, or disseminated infection require therapy with intravenous amphotericin B, which is also used in patients who do not respond to itraconazole.

The treatment of the various manifestations of sporotrichosis will be reviewed. The approach is consistent with the 2007 Infectious Diseases Society of America clinical practice guidelines for the management of sporotrichosis (table 1) [3].

The basic biology, epidemiology, clinical manifestations, and diagnosis of sporotrichosis are discussed separately. (See "Basic biology and epidemiology of sporotrichosis" and "Clinical features and diagnosis of sporotrichosis".)

CHOICE OF ANTIFUNGAL AGENT — The choice of antifungal agent in patients with sporotrichosis is limited. In vitro susceptibility studies and clinical experience support itraconazole as the treatment of choice for patients with most forms of localized sporotrichosis, and amphotericin B as the preferred treatment for patients who are severely ill [3-5]. Fluconazole and ketoconazole are poor second-line choices [6-8]. More detailed information on the use of these agents (eg, monitoring and side effects) is found in the Lexicomp drug information topics within UpToDate and in separate topic reviews. (See "Pharmacology of azoles" and "Pharmacology of amphotericin B".)

In vitro studies have demonstrated good activity for itraconazole and posaconazole, and the minimum inhibitory concentration for terbinafine is low for most isolates [4,5,9-11]. Posaconazole has also been shown to be effective in a murine model of sporotrichosis [12] and has been used successfully to treat a cat [13]. There have also been a few reports of patients who were treated successfully with this agent [14-16]. Several reports have found that voriconazole has poor activity in vitro [4,5,9]. In addition, isavuconazole does not appear very active in vitro against S. schenckii [17]; however, only a small number of isolates have been studied.

One study established epidemiologic cutoff values to help define susceptibility to various antifungal agents by pooling data from 17 different laboratories (301 S. schenckii sensu stricto and 486 S. brasiliensis isolates were collected worldwide) [18]. The most active agents for both species were itraconazole and posaconazole; terbinafine was also active, but too few data were available to calculate a cutoff value for this agent for either species.

APPROACH TO TREATMENT — This section will focus on the management of nonpregnant adults. Additional considerations for the management of pregnant persons and children are discussed below.(See 'Additional considerations' below.)

Lymphocutaneous and cutaneous sporotrichosis

●Initial treatment – Itraconazole is the drug of choice for the treatment of lymphocutaneous and cutaneous sporotrichosis (table 1) [1-3,19,20]. The usual dose is 100 to 200 mg/day orally, and treatment should be continued for two to four weeks after all lesions have resolved, usually for a total of three to six months.

The success rate of this regimen based upon observational studies is 90 to 100 percent [2,20,21]. We favor the 200 mg dose, since some patients will not respond to the lower dose and will require dose escalation. However, in a report about an established epidemic of sporotrichosis associated with exposure to cats in Rio de Janeiro, Brazil, a high rate of success was observed with the 100 mg dose [20]. (See 'Choice of antifungal agent' above.)

●Patients who do not respond to initial therapy – Patients who don't respond to itraconazole at 200 mg/day should be treated with one of the following alternatives:

•Itraconazole 200 mg orally twice daily.

•Terbinafine at high doses (500 mg twice daily). This regimen appears to be effective for sporotrichosis, but few patients have been treated to date [22].

•Saturated solution of potassium iodide (SSKI). The initial dose is five drops in juice or milk three times daily, increasing weekly, as tolerated, to a maximum of 40 to 50 drops in juice or milk three times daily. A once-daily regimen using the same total daily dosage has also been shown to be effective in children and may help improve compliance [23]. Side effects include nausea, rash, metallic taste, fever, and salivary gland swelling.

SSKI had been the preferred treatment until the 1990s, and in some countries it is still used as standard treatment for lymphocutaneous sporotrichosis [23-25]. Although therapy with SSKI is difficult for most patients, it is much less costly than itraconazole

Fluconazole is considered a poor second-line therapy, but if necessary, should be used at a dose of 400 to 800 mg daily [3,6].

●If preferred agents are contraindicated – Local hyperthermia, induced by a variety of different warming devices or baths, has been used successfully and with minimal side effects for cutaneous sporotrichosis [1,26]. Heat therapy could be used, for example, in a pregnant patient who has cutaneous sporotrichosis and cannot safely be treated with any of the oral drugs that are useful for sporotrichosis. (See 'Treatment of pregnant persons' below.)

Pulmonary sporotrichosis — Pulmonary sporotrichosis is difficult to treat, perhaps due to delayed diagnosis or underlying illnesses in infected patients [2,3,6,24,27-29]. In addition to antifungal therapy, surgical resection should be considered, especially for those patients who have a single cavitary lesion [29]. Saturated solution of potassium iodide (SSKI), which has efficacy in lymphocutaneous and cutaneous disease, has not been effective for pulmonary sporotrichosis. Outcomes have improved in recent years, but the response rates are still only about 50 percent.

Severe or life-threatening disease — If the patient is seriously ill, amphotericin B should be used initially; if not, then oral itraconazole can be given at a dose of 200 mg twice daily (table 1) [3]. (See 'Choice of antifungal agent' above.)

When amphotericin B is used, a lipid formulation is preferred at a dose of 3 to 5 mg/kg per day intravenously because of reduced nephrotoxicity compared with amphotericin B deoxycholate [3]. Amphotericin B deoxycholate (0.7 to 1 mg/kg per day intravenously) may be considered in patients without risk factors for renal insufficiency due to its lower cost. (See "Amphotericin B nephrotoxicity" and "Pharmacology of amphotericin B".)

After the patient has shown a favorable response, therapy can be changed to oral itraconazole, 200 mg twice daily. The total duration of therapy should be at least one year and perhaps longer in some patients. Serum levels of itraconazole should be checked after two weeks of therapy to ensure adequate levels.

Mild to moderate disease — Patients with mild to moderate pulmonary sporotrichosis should be treated with itraconazole 200 mg orally twice daily for at least 12 months (table 1). Serum levels of itraconazole should be checked after the patient has taken the drug for at least two weeks to ensure adequate levels.

Osteoarticular sporotrichosis — Almost all patients with osteoarticular sporotrichosis can be treated with itraconazole since the infection is usually chronic and localized (table 1) [1-3,30]. The minimum dose is 200 mg twice daily, and therapy should continue for at least one year [3]. Serum levels of itraconazole should be checked after the patient has taken the drug for at least two weeks to ensure adequate levels. Even if the infection is cured, functional outcome following arthritis due to S. schenckii is often poor. (See 'Choice of antifungal agent' above.)

Amphotericin B is recommended in patients with extensive disease as initial therapy and in those who have not responded to itraconazole [3]. A lipid formulation is preferred at a dose of 3 to 5 mg/kg per day intravenously because of reduced nephrotoxicity compared with amphotericin B deoxycholate [3]. Amphotericin B deoxycholate (0.7 to 1 mg/kg per day intravenously) may be considered in patients without risk factors for renal insufficiency due to its lower cost. (See "Amphotericin B nephrotoxicity" and "Pharmacology of amphotericin B".)

After the patient has shown a favorable response, therapy can be changed to oral itraconazole, 200 mg twice daily.

Intraarticular amphotericin B has been used but is rarely required [31]. Saturated solution of potassium iodide (SSKI), which has efficacy in lymphocutaneous and cutaneous disease, is ineffective in osteoarticular sporotrichosis [3].

Meningeal sporotrichosis — Amphotericin B is the drug of choice for meningeal sporotrichosis (table 1) [32]. A lipid formulation (5 mg/kg per day intravenously for four to six weeks) is preferred because of reduced nephrotoxicity compared with amphotericin B deoxycholate [3]. (See 'Choice of antifungal agent' above.)

Step-down therapy with oral itraconazole, 200 mg twice daily, should be used after initial therapy with amphotericin B is completed. A total of at least 12 months of therapy is required, and for patients with AIDS or ongoing immunosuppression from another cause, chronic suppression with 200 mg itraconazole daily is recommended [3]. Serum levels of itraconazole should be checked after the patient has taken the drug for at least two weeks to ensure adequate levels.

Disseminated sporotrichosis — Treatment of disseminated sporotrichosis includes initial therapy with intravenous amphotericin B followed by step-down therapy with an oral agent after they have shown a favorable response. There are no clinical trials evaluating therapy of disseminated sporotrichosis, so recommendations are based upon case reports [33-35].

●Initial therapy – For patients with disseminated sporotrichosis, especially those who have visceral involvement, we suggest initial treatment with a lipid formulation of amphotericin B (3 to 5 mg/kg per day intravenously) (table 1). We prefer liposomal amphotericin rather than amphotericin B deoxycholate because of reduced nephrotoxicity [3]; amphotericin B deoxycholate (0.7 to 1 mg/kg per day intravenously) may be considered in patients without risk factors for renal insufficiency due to its lower cost.

In one study, patients who had dissemination confined to the skin responded to itraconazole without initial amphotericin B treatment [36]; however, data are limited, and itraconazole should generally be used as step-down therapy.

●Step-down therapy – Patients who have received initial therapy with an amphotericin B formulation can transition to step-down therapy with oral itraconazole (200 mg twice daily) after they have shown a favorable response. Serum levels of itraconazole should be checked at least two weeks into therapy to ensure adequate levels.

A total of at least 12 months of therapy is required and chronic suppression should be considered for patients with AIDS or ongoing immunosuppression from another cause [3]. Suppressive therapy may be discontinued in patients with HIV who are taking antiretroviral therapy, have been treated with itraconazole for at least one year, and have had CD4 counts >200 cells/microL for more than one year [3].

ADDITIONAL CONSIDERATIONS

Treatment of pregnant persons — Pregnant persons should be managed in conjunction with an infectious diseases specialist since azoles should generally be avoided during pregnancy due to their teratogenicity. A discussion of the risks of using azoles during pregnancy is presented elsewhere. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)

Local hyperthermia can be used during pregnancy for those with cutaneous sporotrichosis [37]. (See 'Lymphocutaneous and cutaneous sporotrichosis' above.)

For those with severe sporotrichosis, a lipid formulation of amphotericin B (3 to 5 mg/kg per day intravenously) is suggested because of reduced nephrotoxicity compared with amphotericin B deoxycholate (table 1) [3,37]. Amphotericin B deoxycholate (0.7 to 1 mg/kg per day intravenously) may be considered in patients without risk factors for renal insufficiency due to its lower cost. (See "Amphotericin B nephrotoxicity" and "Pharmacology of amphotericin B".)

Treatment of children — For children with cutaneous or lymphocutaneous sporotrichosis, oral itraconazole 6 to 10 mg/kg up to a maximum dose of 400 mg daily is recommended (table 1) [3,38]. Saturated solution of potassium iodide may be used as an alternative at a dose of one drop in milk or juice three times daily and increased weekly as tolerated to a maximum of one drop per kg or 40 to 50 drops three times daily, whichever is lower [3].

For disseminated sporotrichosis, intravenous amphotericin B deoxycholate 0.7 mg/kg daily should be given initially and can be followed by oral itraconazole 6 to 10 mg/kg up to a maximum of 400 mg daily once clinical improvement has occurred [3]. For patients who require a prolonged course of intravenous therapy, such as those with meningeal sporotrichosis, we suggest a lipid formulation of amphotericin B at a dose of 3 to 5 mg/kg per day, which is less nephrotoxic than amphotericin B deoxycholate.

SUMMARY AND RECOMMENDATIONS

●For lymphocutaneous and cutaneous sporotrichosis, oral itraconazole 200 mg once daily is the drug of choice and should be administered for two to four weeks after all lesions have resolved, usually three to six months. Patients who don't respond to itraconazole at 200 mg/day should be given one of the following alternatives: oral itraconazole at 200 mg twice daily, terbinafine 500 mg twice daily, or saturated solution of potassium iodide. (See 'Lymphocutaneous and cutaneous sporotrichosis' above.)

●For severe pulmonary sporotrichosis, a lipid formulation of amphotericin B should be used initially. After the patient has shown a favorable response, therapy can be changed to oral itraconazole, 200 mg twice daily to complete at least 12 months of therapy. For mild to moderate pulmonary sporotrichosis, oral itraconazole can be given at a dose of 200 mg twice daily for at least 12 months of therapy. (See 'Pulmonary sporotrichosis' above.)

●Osteoarticular sporotrichosis can generally be treated with oral itraconazole 200 mg twice daily for at least 12 months since the infection is usually chronic and localized. Amphotericin B is recommended in patients with extensive disease as initial therapy and in those who have not responded to itraconazole. After the patient has shown a favorable response, therapy can be changed to oral itraconazole, 200 mg twice daily. (See 'Osteoarticular sporotrichosis' above.)

●For meningeal sporotrichosis, a lipid formulation of amphotericin B (5 mg/kg per day intravenously for four to six weeks) is the drug of choice. Step-down therapy with oral itraconazole, 200 mg twice daily, should be used after initial therapy with amphotericin B is completed and therapy should continue for at least 12 months. For patients with AIDS or ongoing immunosuppression from another cause, chronic suppression with 200 mg itraconazole daily is recommended. (See 'Meningeal sporotrichosis' above.)

●For disseminated sporotrichosis, we suggest a lipid formulation of amphotericin B (3 to 5 mg/kg per day intravenously). Step-down therapy with oral itraconazole, 200 mg twice daily, should be started after the patient has shown a favorable response and therapy should be continued for at least 12 months. Chronic suppression should be considered for patients with AIDS or ongoing immunosuppression from another cause. (See 'Disseminated sporotrichosis' above.)

●Serum levels of itraconazole should be checked after the patient has taken the drug for at least at least two weeks for pulmonary, osteoarticular, meningeal, and disseminated sporotrichosis to ensure adequate levels. (See 'Pulmonary sporotrichosis' above.)

●For pregnant women with severe sporotrichosis, a lipid formulation of amphotericin B (3 to 5 mg/kg per day intravenously) is suggested. Azoles should not be given during pregnancy due to their teratogenicity. (See 'Treatment of pregnant persons' above.)

●The treatment of sporotrichosis in children is similar to that in adults, although the dosing differs. (See 'Treatment of children' above.)