Sporotrichosis: a Comprehensive Review on Recent Drug-Based Therapeutics and Management.

Purpose of Review: Over a period of time, sporotrichosis has arisen as one of the leading fungal infections not only in animals but humans also. Several possible reasons that contribute to its emergence include change in epidemiology and distribution, evolutionary changes in taxonomy, and several outbreaks. World Health Organization has identified sporotrichosis as one of the major neglected tropical diseases (NTD) for 2021-2030 under the category of fungal NTDs. Several factors are contributing to increases in morbidity due to sporotrichosis such as delayed diagnosis and unavailability of appropriate antifungal therapy, which lead to redundant and inappropriate treatment with associate costs and adverse effects. Recent Findings: The potassium iodide is the first line of treatment for cutaneous forms while amphotericin B is used for the most severe cases of the disease. The limited medication arsenal, side effects, failure of therapy, and the advent of drug-resistant isolates emphasize the need for the development of new therapeutic options. Several studies are focusing on the development of the new drugs which either used alone or in combination with already available treatment. Along with this, several new antigens have been identified as possible targets for its vaccine development. Summary: The early diagnosis is required for selecting the best possible treatment strategy. The researchers should focus on developing new diagnostic methods and treatment options as well as vaccine development for the better management of sporotrichosis. In the long run, patient education for preventative features to reduce risk and counselling for prolonged therapy will be beneficial.

Introduction

Sporotrichosis is regarded as an environmentally acquired disease. This disease is most typically seen in gardeners and can be contracted through a thorn prick; hence, sporotrichosis is also recognized as rose growers’ sickness or gardener’s disease. A pustule is developed and ulcerates after Sporothrix schenckii inoculation. The infection spreads through the lymphatic circulation, causing a series of cutaneous ulcers. In humans, this lymphocutaneous type is the most prevalent manifestation of Sporothrix schenckii infection. Occasionally, at the site of inoculation, a dermal version of the disease persists [1]. The most typical location for lesions is the arm, but they can appear elsewhere. According to a study, 17% of forestry workers, 10% florists and gardeners, and 16% of other soil-related occupations, such as farmers, accounted for Sporothrix schenckii infections [2]. Infections with Sporothrix schenckii in humans have mostly occurred after touching the plant material; in 1983, for instance, in Oklahoma and New Mexico, 12 cases of dermal sporotrichosis were reported among workers involved in farming activity [3].

In 1988, the most widespread sporotrichosis outbreak in horticulture happened, in that cutaneous sporotrichosis was reported to develop in 84 workers who handled sphagnum moss–packed conifer seedlings [4, 5]. People from 15 states who were involved in forestry, nursery, and gardening were afflicted by the outbreak. It was found that sphagnum moss was the source of sporotrichosis in ten horticulture employees at a Disney World topiary [6]. Besides the horticultural sources of sporotrichosis, the involvement of domestic cats in the Sporothrix schenckii transmission is receiving more attention. The studies on the zoonotic transmission of sporotrichosis imply that this mode of infection may become more common in immunocompromised populations of sporotrichosis in AIDS patients [7, 8]. Sporotrichosis has been considered as an emergent health problem [9]. There are six important factors that affect the rise of zoonotic diseases, which comprise the transportation of animals and humans between geographic locations, augmented animals and human contact, alteration in the environment and husbandry practices, a rising immunocompromised population, improved awareness about the origin of many zoonotic diseases, and the identification of previously unknown organisms.

Etiologic Agent of Sporotrichosis

The causing agent of Sporotrichosis is Sporothrix schenckii which is a dimorphic fungus. It belongs to the Moniliaceae family of the Hyphomycetes class of fungi. There are two important mechanisms of infection of the mycotic agent of sporotrichosis for infection of the mammalian host. First, Sporothrix schenckii can convert into ascomycete teleomorph that helps in its survival on decaying or living plant material. Therefore, it is isolated from decaying foliage such as straw, thorns, wood hay, and soil. Second, the ability to change into a yeast phase after entering the skin through the puncture and cause local lesions and probably systemically in the mammalian host [10].

The Sporothrix schenckii has the dimorphic ability that it remains as a yeast-like form at a temperature between 35 and 37 °C and converts into a mycelial phase (with branching, septate hyphae) at a temperature range between 25 and 30 °C. This nature helps it to survive in the environment and becomes pathogenic in animals [11, 12]. The isolates of Sporothrix schenckii are hyphal mycelia form; nevertheless, it readily adapts to a yeast-like form after subsequent injection into mice or other susceptible mammalian hosts. Conversely, the isolates from animals which is in yeast-like form can easily change into hyphal-conidial form when incubated on suitable media at 25 to 30 °C. However, some Sporothrix schenckii strains grow well at temperatures below or equal to 35 °C and are thought to be involved in localized cutaneous lesion development in animals and humans [13]. Subcutaneous and other rarer forms of infection with Sporothrix schenckii are widespread worldwide in animals and men. There is a wide range of the hosts for infection with this mycotic agent that includes humans, chimpanzees, cattle, dogs, horses, cats, mice, rats, and hamsters [14, 15•].

Prevalence of Sporotrichosis

The actual prevalence of sporotrichosis is unknown because it is not a reportable disease; nevertheless, the disease has been reported in South America (Brazil, Columbia, Mexico, Guatemala, Peru), the USA, Asia (China, Japan, and India,), and Australia [10]. In India, most cases have been reported along the sub-Himalayan regions [16]. After a considerable number of instances were documented in France in the early twentieth century, the number of cases has declined, and the disease is now only seen in Europe on rare occasions [17].

In Peru, the prevalence ranges from 48 to 98 cases per 100 000 people [18], with a mean of 156 cases per 100 000 people in youngsters [19]. In Japan, about 155 cases per year were reported from 1946 to 1982 [20]; however, now, it has been reduced to 50 cases in a year. On the other hand, in Brazil, the cases have increased progressively, from 13 cases to 759 from 1987–1997 to 1998–2004 [21]. In another study from Brazil [22], approximately 2200 cases have been reported between 1998 and 2009, the largest cohort of human sporotrichosis on record worldwide.

Age, Gender, and Occupation Distribution of Sporotrichosis

Although sporotrichosis is thought to be more common in certain age groups and/or genders, the truth is that it can affect anyone, regardless of gender or age. It all depends on exposure. Diverse populations have different occupational and leisure habits, which increase the risk of infection; for example, in Uruguay, males and armadillo hunters have a higher prevalence of sporotrichosis, as the former become infected via scratches obtained while armadillo hunting [23]. In Japan and Northeast India, females have a higher incidence, owing to their greater involvement in agricultural activities [24, 25]. However, in South Africa, as males are more involved in outdoor and mining activities than females, they have a rate of 3:1 [26]. In the Peruvian Andes, compared to adults, children have a threefold higher incidence. Playing in crop fields and on dirty floors in households are two plausible mechanisms of exposure in these children, according to case-controlled studies [19]. Remarkably, even newborns have been known to contract sporotrichosis if they are exposed [27].

Types of Sporotrichosis

Sporotrichosis is broadly classified into two categories.

Cutaneous sporotrichosis

It includes three clinically discrete forms: first is the most common and typical form, cutaneous-lymphatic sporotrichosis, generally seen on arms, legs, and the face of the individual. It represents painful, linearly distributed, and pruriginous ulcerated nodules that might become verrucous plaques in chronic stages. Cutaneous-fixed sporotrichosis is the second form that arises at the inoculation site, also known as sporotrichoid chancre, typically containing a vegetative asymptomatic, slow-growing verrucous lesion, and a squamous, violaceous, or erythematous halo [28–30, 31•]. The third form is cutaneous-disseminated sporotrichosis which is also termed hematogenous sporotrichosis. It is a rare form and is generally present in immunocompromised individuals [10, 29, 32]. The clinical symptoms include verrucous plaques and ulcerated nodules [33]. Most of the cases may be related to cat scratches and develop in individuals with immunocompetency [10, 34].

It can affect any area of the body, including mucous membranes present in various parts of the body like the mouth, pharynx, glans penis and develop ulcerations and sinus plaques in one-third of the patients [35-37]. It can affect joints and bones, causing minor to significant lytic lesions, joint effusions, osteomyelitis, edema, and acute pain. The most commonly affected bones are the carpels, metacarpus, tibia, knee, ulna, and ankle [38-41]. There have been reports of osteoarticular instances or sporotrichoid arthritis without involvement in cutaneous tissue resulting in pulmonary or hematogenous spread [10, 42]. Cutaneous-disseminated sporotrichosis can spread to a variety of organs and systems, e.g., the testes, the central nervous system, leading to fungemia [36, 37, 43].

Extracutaneous sporotrichosis

This occurs when the infection spreads to another part of the body beyond the skin. One of the extracutaneous sporotrichosis is pulmonary sporotrichosis which is a rare form. Only about 100 cases have been reported so far [42, 44, 45] and mostly those are of primary disease type and typically reported in high prevalent areas. It is divided into two clinical forms. First, the chronic form is the most common type. It usually remains asymptomatic (98% of cases). This type has restricted cavitary zones that are indistinguishable from tuberculosis; symptomatic patients have a cough and little expectoration. Condensation or infiltrating miliar type 2 is visible on the radiographs. The acute and progressive variety causes extensive adenopathies in the tracheobronchial lymph nodes, which can lead to bronchial blockage; frequent symptoms include cough with profuse expectoration, dyspnea, and exhaustion. Perihilar lymphadenopathy and, less occasionally, mediastinal enlargement can be seen on a chest X-ray. One of the most lethal consequences of sporotrichosis is central nervous system involvement. It has been recorded in individuals with significant immunosuppression, frequently as a result of leukemia or post-transplantation therapy; nevertheless, the majority of cases are linked to HIV/AIDS and zoonotic outbreaks [36, 46].

Sporothrix brasiliensis is the most prevalent cause of these infections; invasion appears to happen in around 17% of the cases, though the actual incidence is not known [46]. Meningoencephalitis and hydrocephalus are signs of central nervous system involvement; clinical symptoms include headache, neck stiffness, fever, vomiting, and mental disorientation; cryptococcosis is the main differential diagnosis [10, 44]. It is also worth noting that immune reconstitution inflammatory syndrome can arise as a result of antiretroviral therapy; it is believed to affect about 7% of people and can exhibit itself in a variety of ways [37, 46, 47]. Sinuses, lungs, skin, liver, eyes, kidney, heart, and genitalia are all affected by disseminated sporotrichosis (endocarditis). Clinical symptoms vary, and the necropsy is frequently used to detect them [48].

Diagnosis of Sporotrichosis

The disease must be distinguished from other similar diseases like chromoblastomycosis, cutaneous leishmaniasis, cutaneous tuberculosis, blastomycosis, paracoccidioidomycosis, nocardiosis, and atypical mycobacteriosis [49, 50]. Pyoderma gangrenosum also shows similar ulcerating lesions [51]. The detailed scheme of the diagnosis is presented in Fig. 1.

Fig. 1

Detailed scheme of the diagnosis of sporotrichosis

Direct examination

Direct examination of specimens is generally carried out by 10% potassium hydroxide to see budding yeast cells. These cells are smaller in size (2 to 6 µm in diameter) and dispersed, thus not easy to detect by direct examination of human specimens [10]. Because of the scarcity of fungal cells, testing of biopsy or pus specimen smear for causal fungus may not be an appropriate procedure for diagnosis. When examined, the lesion with Gomori-methenamine silver (GMS) or periodic acid-Schiff (PAS) stains after fine-needle aspiration cytology could seldom display yeast cells and cigar-shaped entities, epithelioid cell granuloma, and/or asteroid bodies [52, 53]. On the other hand, the sensitivity/specificity of tissue sample examination by direct microscopy is understudied because it is considered a useless diagnostic tool by most of the researchers due to the scarcity of fungal cells.

Histopathology

The histopathology for sporotrichosis disease is typically vague because of its resemblance with other granulomatous diseases (sarcoidosis, cutaneous tuberculosis, deep fungal infections, and foreign body granulomas) [54]. The foremost histopathologic characteristics of cutaneous sporotrichosis contain epidermal hyperplasia, hyperkeratosis at the edge, central ulceration of epidermis, and acanthosis. In the upper and mid-dermis, there is generally a condensed cellular infiltrate with plasma cells, lymphocytes, and a variable number of eosinophils, giant cells with or without fibrocapillary proliferation, and epithelioid histiocytes [55]. Three concentric zones are indicative of lymphocutaneous sporotrichosis nodules; amorphous debris and polymorphonuclear leukocytes are found in the central necrotic zone (zone of chronic suppuration); epithelioid cells and large cells make up the middle tuberculoid zone. (largely Langhans’ type). The outer zone contains a large number of plasma cells, lymphocytes, and fibroblasts, all of which have notable proliferation and capillary hyperplasia (syphiloid zone) [54, 55]. In histological sections stained with GMS or PAS, the fungal elements can be seen within these zones if they are present. In the gigantic cell’s cytoplasm or in asteroid bodies center, they present as globose, cigar-shaped cells, budding yeast-like cells, or oval to spherical or solitary budding yeast forms [53, 56]. The use of direct immunofluorescence and particular immunohistochemistry procedures to demonstrate them is thought to be more sensitive and specific [57]. Asteroid bodies, on the other hand, are not only associated with the pathogenesis of sporotrichosis and can be seen in various infectious and/or granulomatous disorders [58].

Culture

Although the morphology of the many sporothrix species is similar, the only pathogenic strain is S. schenckii. S. schenckii can be isolated from skin biopsy or other clinical samples (synovial fluid, pus, sputum, and cerebrospinal fluid) and cultured at 25 °C on brain heart infusion agar, Sabouraud’s glucose agar, or Mycosel. The visible growth is achieved in 1 to 2 weeks [53]. Its yeast form is produced by incubating colonies in brain–heart infusion broth or blood glucose-cysteine agar at 37 °C. Generally, S. schenckii is recognized through its typical colony morphology, microscopic appearance, and temperature dimorphism (the ability to live as a yeast at 37 °C and as a mold at 25 °C) [48].

Molecular diagnosis

Because of large differences in specificity and sensitivity, the diagnostic usefulness of all of these tests for sporotrichosis diagnosis is not consistent. Furthermore, due to their inaccessibility for routine diagnostic use, these tests remain of limited usefulness. Nonetheless, they can help to establish a diagnostic suspicion and trigger a more thorough investigation. The antibody titer can be measured by agglutination, immunoblotting, and enzyme-linked immunosorbent assay Furthermore, for identification of S. schenckii in exudates, tissues, and culture, polymerase chain reaction and restriction fragment length polymorphism using calmodulin gene are useful in diagnosis [59, 60]. These are typically suitable diagnosis strategies, particularly when clinical lesions cannot be assessed.

Therapeutic Options

Natural recovery is very rare and treatment is required for most of the patients [61]. Low cost, safety profile, the convenience of administration, and the site of infection (disseminated or localized) are all factors that influence treatment selection. Despite concerns about drug-related side effects, severe and systemic infection will necessitate more vigorous therapy. All therapies should result in the suppression of active infection and S. schenckii eradication from tissues. Treatment for sporotrichosis lasts 3–6 months, although to ensure mycological cure any treatment must be continued for at least 4–6 weeks beyond complete clinical remission. Following adequate therapy for cutaneous sporotrichosis, complete recovery without scarring is anticipated, despite the fact that treatment is time-consuming and costly [62, 63]. Immunocompromised patients typically need suppressive therapy for their whole life. Since its introduction in the nineteenth century, a saturated potassium iodide solution has been the conventional treatment for uncomplicated disease and remains so in poor nations.

Potassium iodide

Oral saturated solution of  potassium iodide (SSKI) continues to be the first-line, low-cost treatment for cutaneous sporotrichosis, particularly when itraconazole is prohibitively expensive, though it is not useful in extracutaneous sporotrichosis. Some researchers believe that this affects granuloma clearance by increasing proteolysis, while others believe it enhances phagocytosis. The actual method of action, however, is uncertain [64]. However, it is not reported to increase S. schenckii killing by monocytes or neutrophils. At 10% SSKI, S. schenckii can grow, indicating that it has no antifungal or anti-fungicidal effect. It has been proposed that there is in vivo conversion of SSKI into iodine by myeloperoxidase and then display its cidal effect, as evidenced by inhibition of cell germination and their direct destruction upon exposure to the iodine-potassium-iodine solution [65].

It remains the most widely practiced treatment in both lymphocutaneous sporotrichosis and fixed cutaneous. It has also been shown to be effective even in circumstances when itraconazole has not worked [33, 66]. There are no particular guidelines/recommendations or treatment plans available. SSKI is commonly administered with 5 drops, comprising 1 g/mL potassium iodide, three times a day orally as a starting dose. There is a gradual rise of dose by 5 drops every day, with 30 to 40 drops maximum, till the complete cure is achieved. Within 2 weeks, the response is visible, and recovery takes 4–32 weeks [67, 68]. However, this schedule is incomprehensible, especially for patients who work outside for a longer period of time, resulting in low compliance.

Some potential side effects include hyperthyroidism or hypothyroidism, iododerma, vasculitis, cardiac irritability, pulmonary edema and angioedema, pustular psoriasis, urticaria, myalgia, lymphadenopathy, and eosinophilia [69]. Patients with a faulty autoregulation system that maintains thyroid hormone production are more likely to develop hypothyroidism as a result of SSKI therapy. In the case of iatrogenic hypothyroidism, stopping SSKI will generally reestablish normal thyroid function within a month. Potassium toxicity can occur in patients on angiotensin-converting enzyme inhibitors, potassium-sparing diuretics, or those with renal impairment, necessitating vigilant monitoring throughout SSKI therapy. SSKI is now classified as a pregnancy category D medication. Patients who acquire “flu-like syndrome” or SSKI hypersensitivity should not resume SSKI therapy since they will have unpleasant effects even at modest dosages [70].

Itraconazole

It is efficacious and well-tolerated at doses of 100–200 mg every day, which has essentially replaced amphotericin B and SSKI in cutaneous and extracutaneous sporotrichosis due to its 90–100% efficacy rates [71]. Itraconazole is also utilized in pulse treatments since it lasts 3–4 weeks in the stratum corneum after it is stopped. In spite of its expensive price, it became the treatment of choice for cutaneous (fixed and lymphocutaneous) and osteoarticular sporotrichosis with success rates ranging from 90 to 100% [72]. According to present guidelines from the Infectious Diseases Society of America, it is given as an oral dose of 200–400 mg for 3 to 6 months and 1 year for disseminated and osteoarticular forms [61]. Despite reported elapses or therapeutic failures, itraconazole is a viable alternative in SSKI-intolerant patients or readily availability/affordability of itraconazole [73]. Epigastric pain, nausea, peripheral edema, hypertriglyceridemia or hypercholesterolemia, and abnormal liver function tests are some of the more common side effects. Another limitation is that the treatment outcome is unpredictable.

Fluconazole

This is a broad-spectrum synthetic bistriazole antifungal drug. It selectively prevents the activity of fungal cytochrome P-450, required for demethylation of sterol C-14-α to ergosterol which is a vital component of the fungal membrane. It provides another valuable therapeutic option either alone or with SSKI orally. Doses range from 150 mg once a week to 200 mg daily for the treatment of both lymphocutaneous and fixed sporotrichosis [74, 75]. Though greater doses of 400 to 600 mg per day are often suggested for the treatment of visceral and osteoarticular sporotrichosis, the response is not encouraging [38]. Vomiting, nausea, diarrhea, headache, abdominal pain, and altered liver enzymes are all typical side effects that rarely need therapy withdrawal. Because of its teratogenic risk, it is not recommended during pregnancy. Fluconazole therapy for sporotrichosis is a second-line therapeutic option for individuals who are itraconazole intolerant because it is somewhat effective [76].

Ketoconazole

It has a poor response rate and is not indicated for the treatment of sporotrichosis. Hepatotoxicity is another constraint for its use, aside from its low efficacy, which is even lower than fluconazole [77].

Terbinafine

Terbinafine is another option for treating itraconazole-resistant cutaneous or lymphocutaneous sporotrichosis or when there is intolerance to itraconazole. It functions well when taken orally and has a low cytochrome P450 enzyme binding affinity. Because it is extremely lipophilic, its antifungal activity is preserved in adipose tissue for a few weeks post-treatment. However, there is no agreement on the best terbinafine dosage and duration schedule. In a limited series or case reports, it has been given alone or in combination with SSKI for the treatment of a few individuals in doses 125–1000 mg/day for 4–37 weeks to attain medical cure. It is now classified as a pregnancy category B medication [78].

Amphotericin B

It is a lipophilic polyene macrolide antibiotic derived from Streptomyces nodosus which is mostly used as an antifungal drug intravenously or topically. It is a treatment of choice for pulmonary/meningeal sporotrichosis and/or severely resistant and disseminated cutaneous sporotrichosis and is safer during pregnancy. It may also be used in individuals with significant osteoarticular sporotrichosis or who are unresponsive to itraconazole therapy, although it is not recommended for intra-articular usage [72]. After the initial 1-mg intravenous testing dose, the recommended adult dose of 0.25 mg/kg/day is raised to obtain the desired dose of 2–3 g. Premedication with antipyretics, sedatives, and corticosteroids can alleviate headache, chills, fever, malaise, and vomiting that may occur following administration of the drug. Hypomagnesemia, hypokalemia, reversible normochromic normocytic anemia, and nephrotoxicity are all common side effects that must be monitored once a week [79, 80]. Amphotericin B’s safety profile has been improved thanks to new lipid formulations that offer higher drug concentrations and reduce nephrotoxicity. Depending on the severity of the disease, it is commonly given at a dose of 3–5 mg/kg of lipid formulation or 0.7 to 1.0 mg/kg/day of amphotericin B deoxycholate. Despite the lack of guidelines due to amphotericin B’s inconsistent therapeutic response, itraconazole is usually prescribed in the early stages of treatment until a good response is achieved, after which itraconazole is prescribed for the remainder of the treatment period [61].

Treatment in pregnancy and pediatric patients

Currently, SSKI is classified as a pregnancy category D medicine, and it is not suggested for use in pregnancy or during lactation due to the possibility of developing thyromegaly and/or neonatal hypothyroidism unless the benefits overshadow the hazards. Terbinafine should not be used during pregnancy, and azoles should be avoided at all costs. Skinny sporotrichosis that does not require immediate treatment can be treated with local heating. Liposomal amphotericin B (3-5 mg/kg/day) can be used to treat sporotrichosis that needs to be treated during pregnancy. It is recommended to postpone the treatment in pregnant patients because there is little risk of sporotrichosis intensifying or spreading to the fetus. The incidence of sporotrichosis in children is less than in adult but are not rare. The children can be treated with half of the adult dose of SSKI, up to 15 drops three times daily, or itraconazole 6–10 mg/kg/day (max 400 mg/day) for 3 to 4 months, just as adults [81]. SSKI, terbinafine, and itraconazole have all been shown to be effective in treating sporotrichosis in infants under the age of 10 months. However, the lack of pediatric antifungal formulations continues to be a problem. Another alternative for children with minimal cutaneous illness is local heat therapy [27].

Treatment of sporotrichosis in patients with immunosuppression

The only sign of an infection spreading to the central nervous system/meninges in immunocompromised people is mild changes in mental status. In these individuals, the medicine of choice is recommended doses of liposomal amphotericin B and will require suppressive therapy with itraconazole 200 mg/day orally for the rest of their lives, as eradication of the pathogen may not be possible [8, 82]. In the patients with AIIDS, initial course of treatment is amphotericin B followed by itraconazole that may be useful for lifelong maintenance therapy in these patients. Furthermore, itraconazole can be used as primary therapeutic option for non-life-threatening disease in those patients who are intolerant to amphotericin B [83].

Treatment of patients with ocular sporotrichosis

The first option for the ocular sporotrichosis is itraconazole at a dose of 100–300 mg/day depending upon the condition and weight of the patient with variable duration of treatment from 4 to 6 months. Another drug is SSKI which is cost effective, has good efficacy, has less side effects, and is mainly used in underdeveloped countries. The 2–20 drops of SSKI three times a day for 2–3 months are used. It also has been administered in combination with itraconazole in those that did not respond well to SSKI alone. The most commonly used treatment for intraocular infections is systemic amphotericin B alone or in combination with an oral antifungal. The suggested dose of amphotericin B is 3–5 mg/kg/day with a variable treatment time depending upon the side effects. Terbinafine is another drug of choice as it has fewer drug interactions and side effects at doses of 250–500 mg/day [84••].

The overview of the treatment option available with the respective dosages and use in different types of patients is provided in Table 1.

Table 1

Overview of the treatment option available

S. no.	Name of drug	Dosages	Used in pregnant patients	Used in pediatric patients	References
1	Potassium iodide (KI)	•5 drops, comprising 1 g/mL KI, three times a day orally as a starting dose •Gradual rise of dose by 5 drops every day, with a 30 to 40 drops maximum	No	Up to 15 drops three times daily	[67, 68]
2	Itraconazole	•Oral dose of 200–400 mg	No	6–10 mg/kg/day (max 400 mg/day)	[61]
3	Fluconazole	•150 mg once a week to 200 mg daily for the treatment of both lymphocutaneous and fixed sporotrichosis •400 to 600 mg per day are often suggested for treatment of visceral and osteoarticular sporotrichosis,	No	Yes	[38, 74, 75]
4	Terbinafine	125–1000 mg/day	No	Yes	[78]
5	Amphotericin B	•Initial 1-mg intravenous testing dose, •0.25 mg/kg/day to 2–3 g •3–5 mg/kg of lipid formulation or 0.7 to 1.0 mg/kg/day of amphotericin B deoxycholate	3-5 mg/kg/ day	–	[61, 79, 80]

Possible Candidates for Vaccine

Although no vaccine is available against sporotrichosis, however, various studies are going on focusing on the vaccine development for sporotrichosis. Identification of a few antigens as a possible candidate for the vaccine may lead to the better and more effective prevention of sporotrichosis. The involvement of proteins found in the sporothrix cell wall that can trigger an immunological response in the host and hence provide an immunoprotective effect has been investigated. In mice afflicted with highly virulent strains of sporothrix, a monoclonal antibody against cell wall Gp70 glycoprotein was employed as a therapeutic vaccination resulting in a reduction in the fungus burden on the organs studied [85]. Few animal studies identified four antigenic molecules (a 44-kDa peptide hydrolase, a 47-kDa enolase, which was predicted to be an adhesin, a 71-kDa protein, and a 9.4-kDa peptide) from S. schenckii cell wall proteins with their possible efficacy and toxicity that represent their potential as a putative candidate for the development of the vaccine. Out of these four antigens, enolase was found to be a possible potential antigenic target against sporotrichosis for vaccinal purposes [86••, 87].

Several other studies have reported additional potential molecules as a target for vaccine development. These include 3-carboxymuconate cyclase (GP60-70), an endoplasmic signal peptidase, and the ZR8 peptide from the GP60-70 protein. Out of these, ZR8 peptide induces the cellular immune response by higher levels of cytokines like IFN-Ɣ, IL-17A, and IL-1β as well as an elevated number of CD4 + T cells. Furthermore, it also increases the number of neutrophils in the lesions responsible for fungus clearance. All, these properties make the ZR8 peptide the best potential vaccine candidate [88-90].

Conclusion

Sporotrichosis is an emerging fungal infection worldwide. Early diagnosis remains a difficulty for treating clinicians, and future research should focus on developing novel diagnostic methods with a faster turnaround time than culture. Over the years, significant progress has been made in the treatment of sporotrichosis. However, it is still undiscovered, and many new therapeutic compounds are now under the preclinical, clinical, and developmental phase. Various treatment options which are available must be used cautiously and efficiently as cost, availability, and the emergence of drug resistance and toxicity in a particular type of sporotrichosis must be considered. Various researchers are now focusing on the development of anti-sporothrix vaccines for prophylactic and therapeutic use against sporotrichosis.