Sporotrichosis

Sporotrichosis commonly follows accidental inoculation of the skin and is characterized by ulceronodule formation at the inoculation site, chronic nodular lymphangitis, and subcutaneous swelling. In the immunocompromised host, disseminated infection can occur from the skin involvement or pulmonary infection. Epidemiology and Etiology Etiology Sporothrix schenckii, a dimorphic fungus, living as a saprophyte on plants in many areas of the world. The tissue form is an oval, cigar-shaped yeast. Sex Males > females, especially disseminated disease. Occupation Occupation exposure important: gardeners, farmers, florists, lawn laborers, agricultural workers, forestry workers, paper manufacturers, gold miners, laboratory workers. In Uruguay, 80% of cases occur after a scratch by an armadillo. Transmission Commonly, subcutaneous inoculation by a contaminated sharp object (rose or barberry thorn, barb, wood splinter) or from sphagnum moss, straw, marsh hay, soils. Rarely, inhalation, aspiration, or ingestion causes systemic infection. Most cases isolated. Epidemics do occur. Cutaneous sporotrichosis in cats has been transmitted to humans. Demography Ubiquitous, worldwide. More common in temperate, tropical zones. Risk Factors For localized disease: diabetes mellitus, alcoholism. For disseminated disease: risk factors for localized disease as well as HIV infection, carcinoma, hematologic and lymphoproliferative disease, immunosuppressive therapy. Pathogenesis After subcutaneous inoculation, S. schenckii grows locally. Infection can be limited to the site of inoculation (plaque sporotrichosis) or extend along the proximal lymphatic channels (lymphangitic sporotrichosis). (Other infections have similar lymphatic involvement, the pattern being referred to as sporotrichoid or resembling lymphatic sporotrichosis.) Spread beyond an extremity is rare; hematogenous dissemination from the skin remains unproven.

The portal for extracutaneous sporotrichosis (e.g., osteoarticular) is unknown but is probably the lung. History Incubation Period 3 weeks (range, 3 days to 12 weeks) after trauma or injury to site of lesion. Lesions are relatively asymptomatic, painless. Afebrile. Physical Examination Skin Lesions Plaque Sporotrichosis Subcutaneous papule, pustule, or nodule appears at inoculation site several weeks after inoculation. Surrounding skin is pink to purplish. In time, skin becomes fixed to deeper tissues. Painless indurated ulcer (Fig. 23-42) may occur, resulting in sporotrichoid chancre. Border ragged and not sharply demarcated. Draining lymph nodes become swollen and suppurative. Crusted ulcers, ecthymatous, verrucous plaques, pyoderma gangrenosumlike, infiltrated papules and plaques may also occur.

Figure 23-42

Sporotrichosis: chancriform type An ulcerated nodule at the site of inoculation on the finger was associated with regional axillary lymphadenopathy. Lymphangitic Sporotrichosis Follows lymphatic extension of local cutaneous type (Fig. 23-43). Proximal to local cutaneous lesion, intervening lymphatics become indurated, nodular, thickened. Figure 23-43

Sporotrichosis: chronic lymphangitic (sporotrichoid) type An erythematous papule at the site of inoculation on the index finger with a linear arrangement of erythematous dermal and subcutaneous nodules extending proximally in lymphatic vessels of the dorsum of the hand and arm.

Disseminated Sporotrichosis

(Fungus disseminates hematogenously to skin, as well as joints, eyes, and meninges.) Crusted nodules, ulcers. Widespread. Distribution Primary lesion most common on dorsum of hand or finger with chronic nodular lymphangitis up arm. Fixed cutaneousface in children, upper extremities in adults. Disseminated sporotrichosis: widespread lesions, usually sparing palms, soles. General Examination Lungs Pulmonary sporotrichosis presents as a single cavitary upper-lobe lesion. Joints Swelling, painful joint(s) (hand, elbow, ankle, knee), often in the absence of skin lesion. Draining sinuses may occur over joints, bursae. Hematogenous dissemination results in skin, bone, muscle, joint, visceral, CNS (chronic meningitis) lesions. Differential Diagnosis Plaque Sporotrichosis Cutaneous tuberculosis, nontuberculous mycobacterial infection, tularemia, cat-scratch disease, primary syphilis, bacterial pyoderma, foreign-body granuloma, inflammatory dermatophytoses, blastomycosis, chromomycosis, mycetoma, leishmaniasis. Chronic Nodular Lymphangitic Sporotrichosis "Common" Infecting Agents Mycobacterium marinum, Nocardia brasiliensis, Leishmania brasiliensis, Francisella tularensis. Laboratory Examinations Touch Preparation In disseminated sporotrichosis (usually with advanced HIV disease), KOH solution added to smear from lesional skin biopsy specimen helps visualize multiple yeast forms. Gram's Stain In disseminated sporotrichosis (usually with advanced HIV disease), smear from crusted lesion shows multiple yeast forms. Dermatopathology

Granulomatous, Langhans-type giant cells, pyogenic microabscesses. Organisms usually rare, difficult to visualize. In the immunocompromised host, yeast appear as myriads of 1- to 3-m by 3- to 10-m cigar-shaped forms. Culture Organism usually isolated within a few days from lesional biopsy specimen. Diagnosis Clinical suspicion and isolation of organism on culture. Course and Prognosis Shows little tendency to resolve spontaneously. Responds well to therapy, but a significant percentage relapse after completion of therapy. Disseminated infection in HIV-infected individuals responds poorly to all forms of therapy. Management1
1

Kauffman CA et al: Clin Infect Dis 30:684, 2000.

Oral Antifungal Agents Itraconazole: 200 to 600 mg qd. Very effective for lymphocutaneous infection; not as effective for bone/joint and pulmonary infection. Fluconazole: 200 to 400 mg/d reported to be effective. Ketoconazole: 400 to 800 mg/d reported to be effective. Terbinafine 1000 mg/d reported to be effective. Saturated solution of potassium iodide: 4.5 to 9 mL/d for adults effective for lymphocutaneous infection; less effective than oral antifungal agents. Adverse events: GI disturbance, acneiform rash. Intravenous Therapy Amphotericin B. For those with pulmonary or disseminated infection or who are unable to tolerate oral therapy for lymphocutaneous disease.

1869 fitzpatricks dermatology in general medicine

DERMATOMIKOSIS PROFUNDA

Sporotrikosis merupakan salah satu penyakit mikosis profunda. Infeksi jamur ini di Indonesia insidensnya tergolong rendah. Akan tetapi di Jepang tergolong endemis dan banyak ditemui pada pekerja tambang. Penyebabnya ialah Sporothrix shenckii, relatif patogen dibanding penyebab mikosis profunda lain; hidup di tempat lembab dan sejuk. Faktor trauma sebagai port d'entre/ tempat masuknya infeksi jamur ini ke dalam tubuh. Apabila sudah kronis, bentuk yang tersering ditemui ialah limfokutan. Diagnosisnya ialah dengan biopsi (PA) dan kultur. Larutan kalium yodida jenuh dan itrakonazol masih dinyatakan efektif untuk mengobati infeksi jamur ini. Dermatomikosis memiliki definisi semua penyakit infeksi jamur yang menyerang kulit sementara itu dermatofitosis adalah penyakit pada jaringan yang mengandung zat tanduk, misalnya stratum korneum pada epidermis, rambut dan kuku yang disebabkan oleh golongan jamur dermatofita. Jamur penyebabnya dibedakan menjadi dua macam, yakni jamur komensal (Candida sp., Malassezia sp.) dan jamur non komensal (dermatofita, jamur kapang/mold lain). Penyakit jamur pada kulit sering termasuk sebagai penyakit akibat kerja. Jamur pada umumnya non patogen, tetapi karena beberapa faktor dapat memicu infeksi terutama pada manusia. Adanya faktor predisposisi dan presipitasi pada pekerja di lingkungan basah misalnya, dapat memicu timbulnya paronikia kandidosis. Adanya trauma merupakan port d'entre (pintu masuk) untuk jamur ke dalam kulit, misalnya pada sporotrikosis pada pekerja tambang. Adanya sumber penularan di lingkungan kerja, misalnya pada tinea pedis di asrama tentara. Faktor predisposisi, presipitasi, trauma, sumber penularan ini semua dapat diperoleh di lingkungan kerja sebagai faktor yang utama. Beberapa dermatomikosis yang bisa merupakan kelainan akibat kerja antara lain adalah dermatomikosis superfisial yang dibagi lagi menjadi dermatofitosis (tinea) dan non dermatofitosis (pitiriasis versikolor, otomikosis, dsb). Sementara itu dermatomikosis profunda (jarang) sebagai contoh adalah kandidosis dan sporotrikosis. Kandidosis juga bisa digolongkan sebagai dermatomikosis superfisial. Kandidosis superfisial merupakan infeksi pada kulit, mukosa dan kuku. Selain itu dapat juga menyerang bronki, jantung, paru, vagina dan kadangkadang dapat menyebabkan endokarditis oleh C. parapsilosis, septikemia oleh C. tropicalis atau meningitis. Penyebab utamanya ialah Candida albicans (dapat juga oleh spesies nonalbicans), flora komensal pada traktus gastrointestinal, mukosa vagina.

Jurnal Abstract Sporotrichosis, caused by several species from the genus Sporothrix, mainly affects men working in agricultural labor. It is reported mostly from endemic regions located in tropical and subtropical

areas. Sporotrichosis usually affects subcutaneous tissue with no symptoms or mild symptoms, but it causes disseminated and even fatal disease if the patient is immunocompromised. Significant progress in the knowledge of etiologic agents of sporotrichosis has been achieved recently, but evaluations of treatment using well-designed clinical trials have been neglected. This article reviews the drugs currently used to treat subcutaneous disease, describing the differences in their efficacy, and reviews recent findings about the proposed new Sporothrix species of clinical interest, as well as the role of melanin as a virulence factor in Sporothrix schenckii.

Keywords Sporotrichosis Sporothrix schenckii Fungal infection Itraconazole Potassium iodide Terbinafine

Introduction

Sporotrichosis is a subacute or chronic disease reported worldwide, caused by fungus from the genus Sporothrix. Cutaneous inoculation of conidia, which are found in the soil and organic matter, is the main route of infection. Sporotrichosis also can occur infrequently if conidia are inhaled, producing pulmonary and disseminated forms. In the developed world, sporotrichosis is uncommon and usually related to trauma occurring during outdoor work (mainly gardening), with sporadic outbreaks associated with handling of contaminated sphagnum moss, hay, or wood [1]. In the past two decades, most reported cases of sporotrichosis have occurred in endemic regions of Brazil, Mexico, India, Japan, and Peru, where an area of the central highlands with an incidence of 48 to 60 sporotrichosis cases per 100,000 persons is considered hyperendemic [13]. Although zoonotic transmission is rare, sporotrichosis can also develop as a consequence of bites, scratches, or direct contact with digging animals or infected cats, as in the ongoing cat-transmitted outbreak in Rio de Janeiro, Brazil. Sporotrichosis was first reported in 1896, but it remains a neglected disease. There are information gaps not only regarding topics of pathogenicity and virulence, but also in the therapeutic area. For example, few randomized clinical trials have evaluated the treatment of sporotrichosis, and although several new drugs were recently incorporated into the armamentarium against fungal infections, only terbinafine has been evaluated in a clinical trial for sporotrichosis treatment. Most therapeutic recommendations are based on case reports, retrospective studies, and a few open-label trials. This review focuses on new developments with impact on clinical management of sporotrichosis and on the identification of gaps that deserve more research.

Etiologic Agent

Until recently, Sporothrix schenckii was considered to be a unique species causing sporotrichosis, but phylogenetic analysis of DNA data from multiple loci of clinical isolates has demonstrated that S. schenckii constitutes a complex of numerous phylogenetic species with different geographic distributions [4]. Using sequence analysis of the calmodulin gene, Marimon et al. [5] reported that S. albicans, S. inflata, and S. schenckii var. luriei are species

different from S. schenckii sensu stricto, and based on phenotypic and genetic approaches, they proposed three new species in the S. schenckii complex: S. brasiliensis and S. globosa, both associated with human infections, and S. mexicana, isolated only from the environment. Though S. brasilensis and S. mexicana are restricted to Brasil and Mexico respectively, S. globosa is widely distributed. On the basis of phenotypic characteristics and multilocus sequence analysis, the same authors later suggested S. luriei, which is a rare human pathogen, as a new species different from S. schenckii [6]. Different species from the S. schenckii complex showed variable virulence when evaluated in a murine model of disseminated infection. S. brasiliensis was the most virulent species, followed by S. schenckii, whereas S. globosa, S. mexicana, and S. albicans demonstrated low or no virulence in this animal model [7].

In Vitro Antifungal Susceptibility Testing

In vitro antifungal susceptibility testing, very helpful for Candida infections, has no clear indication in the case of infections caused by dimorphic fungi. Although the Clinical and Laboratory Standards Institute (CLSI) document M38-A2 for antifungal susceptibility testing of filamentous fungi includes a description of testing S. schenckii in the mycelial phase, the cutoff levels defining resistance have not been established. Nor has it been decided which form (yeast or filamentous) should be tested, nor what the correlation is between in vitro testing results and clinical outcome. Most available data on antifungal susceptibility of S. schenckii was obtained before identification of the several species proposed as members of the S. schenckii complex, and findings were variable and sometimes controversial. It is known that minimum inhibitory concentration (MIC) values are influenced by temperature and by the type of growth phase (mycelia or yeast) used to perform the test [8]. MICs for amphotericin B, 5-flucytosine, ketoconazole, itraconazole, fluconazole, and terbinafine were higher when the filamentous phase was tested [9, 10]. Available data also suggest that human isolates of S. schenckii show lower MICs for itraconazole and terbinafine than animal isolates, most of which are resistant to itraconazole [11]. There are also controversial results on the relationship between susceptibility and clinical forms. Lower susceptibility to itraconazole has been reported among isolates from disseminated forms compared with isolates from lymphocutaneous forms [8], but it has also been reported that there is no association between MIC values and any specific clinical form of the disease [12]. Recently, the response of S. brasiliensis, S. schenckii, S. globosa, S. mexicana, and S. albicans to 12 antifungals was reported [6]. On average, S. brasiliensis showed the best response, and S. mexicana the worst. Among the antifungals tested, terbinafine was the most active for all species, followed by ketoconazole and posaconazole. Itraconazole and ravuconazole showed lower MICs only against S. brasiliensis. Voriconazole showed poor activity, and fluconazole and micafungin were not active against any of the five species tested. Any comparison of in vitro drug susceptibility results or clinical outcomes clearly should identify the species involved, and future treatment recommendations should also be based on knowledge of circulating species in the region where the infection was acquired.

Melanins Role In S. schenckii Pathogenesis

Melanins are pigments formed by the oxidative polymerization of phenolic and/or indolic compounds. In S. schenckii, the 1,8-Dihydroxynaphthalene pathway of melanin biosynthesis leads to melanization of the cell wall of the conidia [13]. Melanin production by S. schenckii was also described on yeast cells, and evidence supports melanin production by hyphal forms [14, 15]. Little information is available regarding participation of melanin as a virulence factor in the pathogenesis of sporotrichosis. A study has found that melanotic S. schenckii strains are more resistant than amelanotic strains to UV light, nitric oxide, and H2O2, and less susceptible to phagocytosis by human monocytes and murine macrophages [13]. The importance of melanin in the pathogenesis of sporotrichosis is also supported by the information that melanized S. schenckii strains had greater tissue invasive capacity, promoting the formation of multifocal granulomas, whereas the albino isolate induced an enhanced inflammatory response, resulting in a restricted and focal granulomatous infiltrate [16]. The property of melanin in binding some drugs can affect the testing of antimicrobial drugs and reduce the activity of antimicrobial therapy. Some studies have shown that Cryptococcus neoformans melanin binds to amphotericin B and caspofungin, and that melanization of C. neoformans and Histoplasma capsulatum are associated with reduced susceptibility to amphotericin B and caspofungin in vitro without affecting azoles [17]. Although the impact of S. schenckii melanin on antifungal susceptibility has not been evaluated, a similar impact could be expected, and future research should consider using it as a potential target of new therapies.

Clinical Aspects

Subcutaneous sporotrichosis typically occurs in low-income men who engage in agricultural labor in tropical and subtropical areas. The lymphocutaneous form is the most frequent (48% to 92%), followed by the cutaneous fixed form (0% to 54%) and the cutaneous disseminated form (0% to 16%). Sporotrichosis lesions are mainly localized on the upper and lower limbs, producing no symptoms or mild symptoms [1, 2, 18]. The associated symptoms and the frequency of cutaneous forms varies among regions. For example, arthralgia, arthritis, erythema nodosum, and erythema multiforme have been reported during the ongoing Brazil epidemic [2], whereas in Colombia, Costa Rica, Porto Alegre (Brasil), and Japan, the cutaneous fixed form is reported more frequently than it is in other countries [1, 18, 19]. Regional variations in clinical characteristics could be explained by differences of virulence and thermotolerance among species and strains, sources and mechanisms of infection, and host immune status. Extracutaneous and disseminated sporotrichosis is uncommon, and it is most likely related to some degree of immunosuppression, including HIV infection, alcoholism, diabetes, and use of corticosteroids or immunosuppressive therapy. Among immunocompromised patients, sporotrichosis involves articulations, lungs, and the central nervous system. Sporotrichosis is an unusual HIV comorbidity: in the years through 2008, only 28 HIV-infected patients suffering cutaneous disseminated and systemic sporotrichosis were reported, most of them with a CD4+ cell count no higher than 100 cells/L [20]. Two additional cases of sporotrichosis meningitis associated with immune reconstitution syndrome recently have been described in AIDS patients [21].

Treatment of Subcutaneous Sporotrichosis

Although spontaneous cure of subcutaneous sporotrichosis has been reported in up to 7.3% of patients [2], sporotrichosis usually requires treatment. The 2007 guidelines from the Infectious Diseases Society of America (IDSA) recommends itraconazole administered for 3 to 6 months as the preferred regimen to treat subcutaneous sporotrichosis [22]; this treatment is expensive for patients living in areas where this disease is prevalent. The same guideline recommends potassium iodide (KI) and terbinafine as alternative drugs, whereas fluconazole should be used only after the other drugs fail.
Itraconazole

Itraconazole impairs the sterol synthesis in fungal cell membranes by inhibiting the enzyme cytochrome P450 lanosterol 14 demethylase, which converts lanosterol to ergosterol, the main sterol in the fungal cell membrane. Itraconazole concentration in the stratum corneum is generally up to10-fold higher than the simultaneous plasma level. MICs for itraconazole ranged from 0.062 to 4.0 g/mL when yeast forms from 18 human and 10 animal isolates of S. schenckii were tested, classifying up to 25% of human isolates and 90% of animal isolates as resistant [11]. MICs were higher, ranging from 0.25 g/mL to more than 16 g/mL, when 18 isolates from disseminated forms and 15 from subcutaneous forms (plus one isolate from household dust) were tested. Isolates from disseminated disease showed higher itraconazole MICs [8]. Itraconazole has shown good activity for experimental cutaneous sporotrichosis when tested in vivo using Wistar rats [23]. Even though there is a lack of large, randomized clinical trials testing itraconazole, it has became the preferred agent to treat most clinical forms of sporotrichosis because of its effectiveness and tolerability evidenced in some open-label studies and retrospective series. Most of these reports were published between 1986 and 1999, usually with limited follow-up time to detect relapses. In the first prospective and open-label study, Restrepo et al. [24] cured all 17 patients with subcutaneous sporotrichosis by administering 100 mg of itraconazole daily for 3 to 6 months. However, in subsequent studies some patients required a higher dose of itraconazole. Conti-Diaz et al. [25] initiated treatment with 200 mg of itraconazole daily in 11 patients, switching three of them to 100 mg after improvement, and initiated itraconazole with 100 mg daily in seven additional patients, increasing the dose to 200 mg daily in five of them after 10 to 15 days because of slow response. All 18 patients were cured with 15 to 75 days of therapy (median, 44.2 days). Nine patients in the United States were cured with itraconazole at doses of 100 to 400 mg daily (mean, 228 mg), although one relapsed twice; the duration of treatment ranged from 3 to 12 months for those who remained free of disease [26]. Of 43 Japanese patients (including 5 children), 88% were cured with itraconazole at a mean dose of 100 mg (range, 25200 mg) during a mean duration of 11 weeks of treatment (range, 335 wk) [27]. Of 165 Brazilian patients, 149 (90.3%) were cured with itraconazole at a dosage of 100 mg daily, administered for a median of 12 weeks (range, 436 wk), but eight patients required an increase in the dose up to 400 mg daily, and seven required a second drug [2]. The current IDSA guideline recommends 200 mg daily for adults, administered until 2 to 4 weeks after resolution of all lesions. This dose is recommended in an attempt to obtain higher success rates. Unresponsive patients should receive 200 mg twice daily. Children should be treated with 6 to 10 mg/kg, up to 400 mg daily [22].

After treatment stops, itraconazole can persist for 3 to 4 weeks in the stratum corneum and for 6 to 12 months in nails, allowing the use of intermittent therapy (pulse regimens) for treating onychomycosis, dermatomycoses, and chromoblastomycosis [28, 29]. Itraconazole in pulses has also been tested for treating sporotrichosis. Five patients with cutaneous sporotrichosis received itraconazole 200 mg twice daily for one week per month; four were cured after 2 to 5 months (mean, 3.5 pulses) [30]. Recently, a randomized, open-label clinical trial assessed pulsed therapy using itraconazole at a dosage of 200 mg twice daily for 1 week and off for 3 weeks, compared with continuous daily therapy using 100 mg of itraconazole. At weeks 12, 24, and 48, the cure rates were 77.3%, 81.8%, and 81.8% among 22 evaluable participants in the pulsed therapy arm, versus 79.2%, 91.7%, and 95.8% among 24 participants in the daily therapy group. The mean duration of treatment was 2.650.81 pulses and 2.802.33 months; the rates of adverse effects were 4.5% and 16.7%. The authors concluded that there were no significant differences between the pulsed therapy and the daily therapy in efficacy, safety, or duration of treatment [31], but a larger clinical trial is needed to confirm these findings. Itraconazole has a good safety profile, with no serious adverse events related to the drug reported during the treatment of sporotrichosis. Reported adverse events possibly related to itraconazole during treatment of subcutaneous sporotrichosis are nausea, vomiting, elevation of transaminases and bilirubin levels, headache, epigastralgia, and peripheral edema [2426]. Monitoring of liver function is recommended in all patients receiving itraconazole, because some rare cases of serious hepatotoxicity have been observed in patients receiving this drug to treat other fungal infections. In addition, itraconazole presents numerous interactions with other drugs, and there is considerable intrapatient and interpatient variability of plasma drug concentrations that limit its use; this variability has led to a recommendation that plasma drug levels be monitored during itraconazole therapy in patients with life-threatening fungal infection, suspected drug failure, or infection relapse.
Potassium Iodide

Even though KI has been used to treat subcutaneous sporotrichosis since the early 1900s, its precise mechanism of action is still unknown. It is known that KI inhibits the growth of the filamentous phase of S. schenckii [32], and yeast germination is markedly inhibited by iodine in concentrations ranging between 0.63 g/mL and 5.0 g/mL, destroying the inner structures of the yeast cells only at the higher concentration. The former evidence leads to the assumption that iodine causes rapid destruction of fungal cells during treatment [33]. Data on KI efficacy and safety are derived mostly from retrospective studies and a single randomized clinical trial evaluating two regimens of KI. No adequately designed clinical trial has compared the efficacy and safety of KI with that of the preferred therapy. The success rate of KI in treating subcutaneous sporotrichosis has been reported to be 89% to 100%, with only a few failures unrelated to lack of compliance or loss of follow-up [34, 35]. Because of its efficacy rate and accessible price, KI is still the regimen of choice for treating subcutaneous sporotrichosis in Brasil, Colombia, Peru, India, Japan, and other countries with endemic regions [3, 18, 19, 36]. The recommended regimen of KI for adults is to use a saturated solution of potassium iodide (SSKI) initiated at a dosage of 5 drops three times per day, increasing as tolerated to 40 to 50 drops three times per day. Children should begin with one drop three times daily, increasing to a maximum of one drop per kg of body weight or 40 to 50 drops three times daily, whichever is lowest. Treatment should be maintained until 2 to 4 weeks after lesions are healed [22].

The duration of treatment with KI varies and is independent of the cutaneous clinical forms; most patients require less than 3 months of therapy. The mean duration of treatment has ranged from 32.3 days [37] to 8.7 weeks [35], which on average is usually shorter than the duration required when itraconazole or terbinafine is used [34, 36]. The main limiting factor for the use of KI is the presence of adverse events, which are common during therapy and affect treatment compliance. The rate of adverse events was reported to be as low as 9.8% among 303 retrospectively evaluated patients, including 61 considered noncompliant or lost to follow-up [19]; but the rate was up to 42% among 28 patients prospectively evaluated while receiving KI three times per day, and 61% among 29 receiving KI in a single daily dose [37]. The most common adverse events include nausea, vomiting, headache, abdominal pain, gastric discomfort, metallic taste, soft stools, diarrhea, rhinorrhea, and flulike symptoms. Less common but more severe events, leading to treatment discontinuation or noncompliance, are severe urticaria and erythema nodosum [37]. Looking for simplified regimens, a randomized clinical trial involving 57 pediatric patients tested a three-times-per-day regimen against a one-time-per-day regimen. The observed efficacy and time to cure were comparable in both arms, but the frequency of adverse events was higher in the one-time-per-day group (61% vs 42%), though the difference was not statistically significant [37]. In summary, KI is an effective alternative for treating subcutaneous sporotrichosis, even though its mechanism of action is unknown. Because of the extensive use of KI in the developing world, where most cases occur, it is important to better evaluate the efficacy and safety of KI in comparison to the preferred drug, itraconazole; to evaluate new formulations with better taste; and to confirm the efficacy of the once-per-day regimen. In addition, future clinical trials should include follow-up periods long enough to properly detect relapses.
Terbinafine

Terbinafine, an allylamine-derived antifungal agent, was the first orally active antifungal agent with a primary fungicidal action. It inhibits ergosterol biosynthesis at the level of squalene epoxidation, producing accumulation of squalene and depletion of ergosterol, which is an essential component of fungal cells. Terbinafine does not interfere with steroid hormone production in the host and has little potential to interact with other medications. Terbinafine is highly lipophilic, and its slow depuration from the adipose tissue maintains fungicidal activity for some weeks after stopping the treatment, allowing onychomycosis and dermatomycosis to be effectively treated with short regimens. Although human and animal isolates of S. schenckii have demonstrated good in vitro susceptibility to terbinafine, with MICs ranging from 0.007 to 0.50 g/mL [11], terbinafine did not reduce mortality or dissemination of this infection despite a good plasma drug level in a murine model of systemic sporotrichosis [38]. Neither was it effective at doses of 20 and 30 mg/kg for the treatment of experimental cutaneous sporotrichosis in Wistar rats using an isolate from a domestic cat with cutaneous sporotrichosis [23]. Terbinafine is the only antifungal drug evaluated for the treatment of cutaneous sporotrichosis in a multicenter, double-blind, randomized clinical trial comparing two doses. This study demonstrated that 500 mg of terbinafine administered twice daily for a mean of 13.96.7 weeks cured 87% (n=35) of patients; this regimen was more effective than 250 mg administered twice daily for 17.75.8 weeks, which cured 52% (n=28) of patients [39].

Although 500 mg of terbinafine twice daily is currently considered an alternative for the treatment of cutaneous sporotrichosis, some studies have reported successful treatment of sporotrichosis with lower doses. Five patients from South Africa were cured with 250 mg twice daily administered for 8 to 37 weeks (mean, 18; median, 14) [40], and 12 of 16 Japanese patients were cured with 125 mg daily (although the dose was raised to 250 mg daily in two of them), administered for a range of 10 to 21 weeks [36]. Also, 86% of 45 Brazilian patients with contraindications for itraconazole treatment were cured with terbinafine, 250 mg daily [41]. Favorable responses with dosing lower than 500 mg twice daily could be explained by involvement of different Sporothrix species or strains.
Fluconazole, New Antifungal Drugs, and Physical Methods

Fluconazole has limited in vitro activity against S. schenckii [42], and the limited published evidence shows a response rate ranging from 63% to 71% [22]. For these reasons, fluconazole (400 mg daily) should be used only for patients who cannot tolerate the recommended therapies. At this dose, cure is attained at a mean of 6.4 months (range, 116 mo) [43]. Among new antifungals, only posaconazole has good in vitro activity against five species from the S. schenckii complex, and ravuconazole has shown good in vitro activity only against S. brasiliensis [42]. Echinocandins have no activity, and voriconazole has poor activity [42, 44]. There are currently no clinical data to support the use of these new antifungals in patients with sporotrichosis. Combining antifungal drugs with thermotherapy has been proposed for the fixed cutaneous clinical form of sporotrichosis with small lesions. Thermotherapy can also be used as the only treatment in pregnant women with cutaneous sporotrichosis. The local hyperthermia appears to act on S. schenckii by enhancing the intracellular killing capability of polymorphonuclear neutrophils. Temperatures about 45C can be achieved using pocket warmers, heat compresses, and infrared and far infrared rays. Cure rates of 71% were achieved using different methods of thermotherapy in 14 patients [45].
Treatment of Extracutaneous and Disseminated Sporotrichosis

Treatment of extracutaneous and disseminated sporotrichosis is challenging, with low rates of success. Current recommendations for treating extracutaneous and disseminated sporotrichosis are based on a few open-label treatment trials and case reports, and on an expert panel. In short, itraconazole is recommended for osteoarticular or mild pulmonary sporotrichosis, at a dosage of 200 mg twice daily for at least 12 months. Surgery could be needed if skin fistulas develop despite itraconazole treatment of osteoarticular disease. Amphotericin B lipid formulation (35 mg/kg daily) is recommended for osteoarticular sporotrichosis not responding to itraconazole, for cases of moderate or severe pulmonary involvement, and for meningeal or disseminated disease. If amphotericin B lipid formulation is not available, an alternative treatment is amphotericin B deoxycholate at a dosage of 0.7 to 1.0 mg/kg daily. After patients show a beneficial response to amphotericin B, they can be shifted to itraconazole (200 mg twice daily) until the completion of at least 12 months of treatment. The serum level of itraconazole should be monitored to ensure that it is at least 1 g/mL.

The response of sporotrichosis to therapy with amphotericin B or itraconazole in patients with HIV infection is low. When these drugs were used as primary therapy, cure was obtained in 3 of 16 patients treated with amphotericin B and 2 of 5 patients treated with itraconazole [20]. The updated guidelines from the IDSA recommend treating any form of sporotrichosis in HIV-infected patients with itraconazole if the patient is not severely ill, or with amphotericin B lipid formulation for those who are critically ill. The recommendation of the lipid formula is based on expert opinion and on results obtained from treating other systemic mycoses in HIV-infected patients. Subsequent suppressive therapy with itraconazole is required until reconstitution of the immune system is achieved [22]. Because of the rarity of extracutaneous and disseminated clinical forms of sporotrichosis, designing a proper clinical trial to identify the best treatment is challenging. Early treatment is more likely if physicians are knowledgeable about clinical aspects of this disease and if new diagnostic tools, with shorter turnaround time than cultures, are available. It is hoped that discovery of new drugs acting on common fungal targets will improve the treatment of life-threatening sporotrichosis.

Conclusions

S. schenckii is no longer a single species causing sporotrichosis. Using molecular tools, it has been demonstrated that S. schenckii constitutes a complex of numerous phylogenetic species with different geographic distributions. It has also been demonstrated that different species of Sporothrix show different in vitro responses to antifungal drugs and show dissimilar virulence. This new knowledge will help in understanding the variability observed in response to therapy among patients from different regions or countries, and will make identification of the species involved a strict requirement for future sporotrichosis clinical trials. Sporotrichosis remains incompletely studied, especially in the therapeutic field. Only a few properly designed clinical trials support the current recommendations for treating sporotrichosis, and the need remains for new therapies that can cure subcutaneous disease with a shorter duration of treatment and for new therapies to treat disseminated forms more effectively. Though itraconazole is recommended as the first-line drug for the treatment of subcutaneous sporotrichosis, KI is still the first choice in most developing countries, mainly because of its lower cost, despite the complexity of its administration regimen and the frequency of adverse events. For this reason, researchers should try to identify new KI formulations with better taste to improve compliance. Finally, new therapeutic targets, such as the inhibition of melanin formation, require more research.
Disclosure No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading

Recently published papers of interest have been highlighted as Of importance 1. Bustamante B, Campos PE. Endemic sporotrichosis. Curr Opin Infect Dis 2001; 14:145149.

2. Barros MB, Schubach Ade O, do Valle AC, et al. Cat-transmitted sporotrichosis epidemic in Rio de Janeiro, Brazil: description of a series of cases. Clin Infect Dis 2004; 38:529535.

3. Pappas PG, Tellez I, Nolazco D, et al. Sporotrichosis in Peru: Description of a hyperendemic area. Clin Infect Dis 2000; 30:6570.

4. Marimon R, Gen J, Cano J, et al. Molecular phylogeny of Sporothrix schenckii. J Clin Microbiol 2006; 44:32513256.

5. Marimon R, Cano J, Gen J, et al. Sporothrix brasiliensis, S. globosa, and S. mexicana, three new Sporothrix species of clinical interest. J Clin Microbiol 2007; 45:31983206.

6. Marimon R, Gen J, Cano J, Guarro J. Sporothrix luriei: a rare fungus from clinical origin. Med Mycol 2008; 46:621625.

7. Arrillaga-Moncrieff I, Capilla J, Mayayo E, et al. Different virulence levels of the species of Sporothrix in a murine model. Clin Microbiol Infect 2009; 15:651655. The authors demonstrate for first time that species of the S. schenckii complex have different degrees of virulence.

8. Trilles L, Fernndez-Torres B, Dos Santos Lazra M, et al. In vitro antifungal susceptibilities of Sporothrix schenckii in two growth phases. Antimicrob Agents Chemother 2005; 49:39523954

9. Kohler LM, Soares BM, de Assis Santos D, et al. In vitro susceptibility of isolates of Sporothrix schenckii to amphotericin B, itraconazole, and terbinafine: comparison of yeast and mycelial forms. Can J Microbiol 2006; 52:843847.

Sporotrichosis

Definition
Sporotrichosis is a chronic infection caused by the microscopic fungus Sporothrix schenckii. The disease causes ulcers on the skin that are painless but do not heal, as well as nodules or knots in the lymph channels near the surface of the body. Infrequently, sporotrichosis affects the lungs, joints, or central nervous system and can cause serious illness.

Description
The fungus that causes sporotrichosis is found in spagnum moss, soil, and rotting vegetation. Anyone can get sporotrichosis, but it is most common among nursery workers, farm laborers, and gardeners handling spagnum moss, roses, or barberry bushes. Cases have also been reported in workers whose jobs took them under houses into crawl spaces contaminated with the fungus. Children who played on baled hay have also gotten the disease. Sporotrichosis is sometimes called spagnum moss disease or alcoholic rose gardener's disease.

Causes and symptoms

The fungus causing sporotrichosis enters the body through scratches or cuts in the skin. Therefore, people who handle plants with sharp thorns or needles, like roses, barberry, or pines, are more likely to get sporotrichosis. Sporotrichosis is not passed directly from person to person, so it is not possible to catch sporotrichosis from another person who has it. The first signs of sporotrichosis are painless pink, red, or purple bumps usually on the finger, hand, or arm where the fungus entered the body. These bumps may appear anywhere from one to 12 weeks after infection, but usually appear within three weeks. Unlike many other fungal infections sporotrichosis does not cause fever or any feelings of general ill health. The reddish bumps eventually expand and fester, creating skin ulcers that do not heal. In addition, the infection often moves to nearby lymph nodes. Although most cases of sporotrichosis are limited to the skin and lymph channels, occasionally the joints, lungs, and central nervous system become infected. In rare cases, death may result.

People who have weakened immune systems, either from a disease such as acquired immune deficiency syndrome (AIDS ) or leukemia, or as the result of medications they take (corticosteroids, chemotherapy drugs), are more likely to get sporotrichosis and are more at risk for the disease to spread to the internal organs. Alcoholics and people with diabetes mellitus or a pre-existing lung disease are also more likely to become infected. Although sporotrichosis is painless, it is important for people with symptoms to see a doctor and receive treatment.

Diagnosis
The preferred way to diagnose sporotrichosis is for a doctor to obtain a sample of fluid from a freshly opened sore and send it to a laboratory to be cultured. The procedure is fast and painless. It is possible to confirm the presence of advanced sporotrichosis through a blood test or a biopsy. Doctors may also take a blood sample to perform tests that rule out other fungal infections or diseases such as tuberculosis or bacterial osteomyelitis. Dermatologists and doctors who work with AIDS patients are more likely to have experience in diagnosing sporotrichosis. In at least one state, New York, the laboratory test to confirm this disease is provided free through the state health department. In other cases, diagnosis should be covered by health insurance at the same level as other diagnostic laboratory tests.

Treatment
When sporotrichosis is limited to the skin and lymph system, it is usually treated with a saturated solution of potassium iodine that the patient dilutes with water or juice and drinks several times a day. The iodine solution can only be prescribed by a physician. This treatment must be continued for many weeks. Skin ulcers should be treated like any open wound and covered with a clean bandage to prevent a secondary bacterial infection. The drug itraconazol (Sporanox), taken orally, is also available to treat sporotrichosis. In serious cases of sporotrichosis, when the internal organs are infected, the preferred treatment is the drug amphotericin B. Amphotericin B is a strong anti-fungal drug with potentially severe toxic side effects. It is given intravenously, so hospitalization is required for treatment. The patient may also receive other drugs to minimize the side effects of the amphotericin B.

Alternative treatment
Alternative treatment for fungal infections focuses on maintaining general good health and eating a diet low in dairy products, sugars, including honey and fruit juice, and foods, such as beer, that contain yeast. This is complemented by a diet high in raw food. Supplements of and vitamins C, E, and A, B complex, and pantothenic acid may also be added to the diet, as may Lactobacillus acidophilus, bifidobacteria, and garlic capsules. Fungicidal herbs such as myrrh (Commiphora molmol ), tea tree oil (Melaleuca spp.), citrus seed extract, pau d'arco tea, and garlic (Allium sativum ) may also be applied directly to the infected skin.

Prognosis
Most cases of sporotrichosis are confined to the skin and lymph system. With treatment, skin sores begin healing in one to two months, but complete recovery often takes six months or more. People who have AIDS are also more likely to have the fungus spread throughout the body, causing a life-threatening infection. In people whose bones and joints are infected or who have pulmonary lesions, surgery may be necessary.

Prevention
Since an opening in the skin is necessary for the sporotrichosis fungus to enter the body, the best way to prevent the disease is to avoid accidental scrapes and cuts on the hands and arms by wearing gloves and long sleeves while gardening. Washing hands and arms well after working with roses, barberry, spagnum moss, and other potential sources of the fungus may also provide some protection.

KEY TERMS
Acidophilus The bacteria Lactobacillus acidophilus, usually found in yogurt. Bacterial osteomyelitis An infection of the bone or bone marrow that is caused by a bacterium. Bifidobacteria A group of bacteria normally present in the intestine. Commercial supplements are available. Corticosteroids A group of hormones produced naturally by the adrenal gland or manufactured synthetically. They are often used to treat inflammation. Examples include cortisone and prednisone. Lymph channels The vessels that transport lymph throughout the body. Lymph is a clear fluid that contains cells important in forming antibodies that fight infection.