Eumycetoma

INTRODUCTION — Mycetoma (also termed ‘Madura foot’) is a chronic skin and soft tissue infection resulting in a mass, sinus formation, and discharge with grains (which contain colonies of the causative organism); it extends to adjacent tissues in some cases [1].

Mycetoma can be caused by fungi (eumycetoma) or bacteria (actinomycetoma, most commonly actinomyces, streptomyces, or Nocardia). Issues related to eumycetoma will be reviewed here; issues related to actinomycetoma are discussed separately. (See "Treatment of nocardiosis", section on 'Mycetoma' and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Skin'.)

Eumycetoma ("mycotic mycetoma") usually occurs on the foot but other parts of the body can also be affected; The causative microorganisms likely gain entry via a thorn prick or other skin lesion. The disease typically occurs in resource-limited settings and is on the World Health Organization's list of neglected diseases [2].

EPIDEMIOLOGY — Most cases of eumycetoma occur among individuals living in resource-limited countries in tropical and subtropical regions, although cases have been reported worldwide (including in temperate regions). The true prevalence is not known since it is not a reportable disease. Most published eumycetoma cases come from Africa and India, while actinomycetoma cases seem to be most common in Latin America [1-6].

Eumycetoma typically affects healthy adult men such as field laborers or farmers who work in rural areas and have frequent exposure to soil. The mean age is 33 (range, 8 to 68 years); pediatric cases are rare. The male to female ratio is about 3:1 to 5:1.

Eumycetoma among animals is rare but has been reported in horses, water buffalo, and dogs. There are no known cases of zoonotic or laboratory acquisition of eumycetomas nor has person-to-person transmission been described.

PATHOGENESIS — The pathogenesis of eumycetoma infection is not fully understood. Many individuals are exposed to eumycetoma agents but only a few develop the disease. Risk factors appear to include environmental exposure to pathogenic organisms and genetic predisposition to infection.

Eumycetoma begins with traumatic inoculation of the organism into cutaneous and/or subcutaneous tissues. Trauma may be minor (due to thorns, splinters, or other objects), and patients may not recall a specific injury [7-9].

In general, infection remains localized. Grains (colonies of infecting organisms, with melanin or other substances) are formed in infected tissues; free filaments do not develop. The grains are partially broken down via a neutrophil-mediated inflammatory reaction; their remains perpetuate an inflammatory response. An epithelioid granuloma develops via recruitment of macrophages, which form multinucleated giant cells and clear dead neutrophils and grain fragments [10]. The role of melanin production is not fully understood; it has been linked to virulence and pathogenicity. Melanization appears to protect the organism from strong oxidants and azole drugs in vitro [11]. The host produces cytokines and enzymes, which have been shown to degrade the chitin contained in grains of Madurella mycetomatis, the most common cause of eumycetoma [12].

Genetic predisposition to development of eumycetoma or actinomycetoma may be an important factor in pathogenesis. In endemic areas, many individuals have antibodies to M. mycetomatis. It has been postulated that some individuals lack sufficient neutrophil function to clear the organism and thus develop disease [13]. In addition, polymorphism in the gene for chitotriosidase that results in enzyme inactivity has been associated with increased risk for mycetoma [12].

Although eumycetoma frequently develops in the absence of immunosuppression, a number of cases have been reported in immunocompromised patients. These include one case due to Exophiala jeanselmei in a patient with an idiopathic CD4+ T cell lymphocytopenia and another case due to Madurella spp in a patient with acute myeloid leukemia undergoing chemotherapy [14,15]. Eumycetoma has also been described in solid organ transplant recipients; most had a good outcome with antifungal therapy and/or surgical management despite immunosuppressive therapy [16-19]. One series described both eumycetoma and actinomycetoma in association with diabetes (9 out of 26 cases) [20].

The role of the immune response in the setting of eumycetoma is not fully understood. Some studies have described a reduction in cell-mediated immune response among patients with eumycetoma or actinomycetoma [21,22]; another failed to demonstrate any immune alteration [23]. The small number of participants in these studies and the mixing of eumycetoma and actinomycetoma cases preclude drawing definitive conclusions.

MICROBIOLOGY — Organisms capable of causing eumycetoma are distributed worldwide and include at least 44 hyaline and pigmented species of molds (table 1) [24-36]. Microbiologic diagnosis and characterization of the exact organism causing eumycetoma is difficult, and the necessary identification tools are often not available in endemic areas.

The predominant pathogen is M. mycetomatis, which, along with Trematosphaeria grisea (formerly Madurella grisea), Falciformispora senegalensis (formerly Leptosphaeria senegalensis), and Scedosporium apiospermum species complex (formerly Pseudallescheria boydii/S. apiospermum) are responsible for more than 90 percent of reported eumycetoma cases worldwide (figure 1) [37].

Grains contain aggregated colonies of the causative microorganisms encapsulated in a cement-like material, with melanin or other substances; they may be observed macroscopically or microscopically. Some species produce grains with thickened fungal cell walls; these include S. apiospermum species complex, Fusarium spp, Acremonium killiense, and M. mycetomatis [38]. Cell-wall thickening may be an important factor in the difficulties associated with obtaining cultures from grains.

Traditionally, black-grain eumycetomas caused by Madurella have been attributed to M. mycetomatis as this was the only accepted species in the genus beside T. grisea [39]. However, use of molecular techniques has identified three additional species of Madurella: Madurella fahalii, Madurella pseudomycetomatis, and Madurella tropicana [26,40]. M. mycetomatis remains the prevalent species causing mycetoma worldwide; the others are rare. M. fahalii has been reported from Sudan, Mali, Saudi Arabia, and Canada [26,39], and M. tropicana has been reported in Sudan [26,39].

The local prevalence of specific pathogens is determined by ecologic conditions including temperature, rainfall, type of soil, prevalent vegetation, and pollution [41]. M. mycetomatis is common in arid zones [42], whereas S. apiospermum species complex is common in temperate rainy areas [20,43]. S. apiospermum species complex are also found more frequently in nitrogen-rich environments with organic pollution from human, poultry, and cattle manure [44]. In Africa, M. mycetomatis and F. senegalensis are the most common pathogens; T. grisea and S. apiospermum species complex are less frequent pathogens. In South America, T. grisea is the most prevalent pathogen, followed by M. mycetomatis and S. apiospermum species complex. In North America, S. apiospermum species complex are the most prevalent pathogens, followed by T. grisea. Studies using molecular techniques demonstrate that M. pseudomycetomatis could be the dominant Madurella species in South and Central America [45].

Soil is the natural reservoir for most of these agents. M. mycetomatis, T. grisea, S. apiospermum species complex, Phialophora verrucosa, and Neotestudina rosatii have been isolated from soil samples [46,47]. It has been demonstrated that thorns serve as mechanical vectors only after they are contaminated with soil. This was illustrated in an evaluation of thorns in the Senegal River region; culprit organisms were demonstrated on fallen Acacia thorns but not on green thorns (eg, thorns not contaminated with soil) [48,49].

CLINICAL MANIFESTATIONS

●Definition and incubation period − Eumycetoma is a chronic subcutaneous mycotic infection of the skin and soft tissue; in some cases, it extends to adjacent tissues. Uncovered areas that are exposed to trauma and soil are most often affected [50]. The incubation period between inoculation and clinical manifestations is uncertain, and many patients may not recall a specific predisposing injury.

●Involved sites − Eumycetoma most frequently involves the feet, followed by legs and hands (80, 7, and 6 percent, respectively, in one study) [51]. Workers who carry vegetable matter over exposed areas of the back or abdomen are susceptible to eumycetoma in these regions; direct spread to the vertebral bodies and the spinal cord can occur [1,52]. Less frequent sites include buttocks, forearms, the groin/perineum, head/neck, and testicles [7,20,51,53-56]. The occurrence of multiple eumycetomas is rare and should prompt consideration of alternative diagnoses [57].

●Clinical findings − Mycetoma (eumycetoma or actinomycetoma) may present with a characteristic triad of tumor (painless firm subcutaneous mass), sinus tracts, and discharge-containing macroscopic or microscopic grains (picture 1) [1].

Initially, lesions are painless and commence as slowly growing indurated subcutaneous nodules (picture 2 and picture 3). Extension of lesions occurs due to nodular swelling and coalescence, forming large tumors that evolve into necrotic abscesses and draining sinus tracts, which may produce a discharge that contains grains (picture 4 and picture 5).

The clinical appearance may underestimate the extent of involvement; undetected subcutaneous tracts can extend beyond the limits of the mass. (See 'Grain identification and fungal culture' below.)

●Depth of involvement − Eumycetomas are usually confined to subcutaneous tissues but can involve fascia, bone, and regional lymph nodes via contiguous dissemination [58]. Hematogenous spread may also be possible but is rare [59]. Bone involvement is more frequent in the setting of longstanding lesions [7,60]. Lesions in areas with thin subcutaneous tissue (eg, feet, hands, and skull) are more likely to progress to bone involvement. Bone invasion can result in cavities filled with grains that contain fibrous tissue, which provides stability; therefore, pathologic fractures are uncommon. Bone involvement portends a poor prognosis and requires a longer course of therapy.

●Complications − Eumycetoma lesions may evolve over months, years, or decades. In the absence of treatment, they may become deforming and disabling tumors (picture 5). Complications include fibrosis, ankylosis, and lymphedema caused by lymphatic obstruction. Other rare complications have been observed; these include massive destruction of a joint, pulmonary eumycetoma secondary to a subcutaneous lesion, and bronchopleural cutaneous fistula [61-64].

Nerves and tendons are rarely affected until late in the disease; although the lesion may be tender, pain is not a typical feature. The presence of pain is often associated with secondary bacterial infection (commonly caused by Staphylococcus aureus); in one series that included 98 cases of mycetoma, of which 90 percent were eumycetoma, this complication was observed in 66 percent of cases [65].

DIAGNOSIS

General approach

●Clinical diagnosis – In endemic areas with limited diagnostic tools, the diagnosis of mycetoma is often made clinically; a clinical diagnosis may be established in patients with the characteristic triad of tumor, sinus tracts, and discharge-containing grains. Presence of black grains indicate a fungal etiology (establishing a diagnosis of eumycetoma); presence of white to yellow grains may indicate fungal or bacterial infection (eg, eumycetoma or actinomycetoma).

In the absence of sinus tracts or macroscopic grains, further diagnostic evaluation must be pursued, for mycetoma as well as other conditions. (See 'Differential diagnosis' below.)

●Definitive diagnosis − The evaluation usually consists of ultrasonography (demonstrating grains and/or cavities), followed by fine needle aspiration (FNA) to obtain material for histopathologic evaluation [66,67]. FNA is preferred over extrusion of sinus material because sinus material is more likely to be nonviable and/or contaminated.

A definitive diagnosis of eumycetoma may be established by histopathologic evaluation demonstrating hyphae (facilitating discrimination between fungal and bacterial etiologies). Culture is required for species identification. Molecular tools are promising but costly and not universally available.

Diagnostic tools

Radiographic imaging

●Choice of modality − Useful radiographic tools for evaluation of suspected eumycetoma include ultrasonography, conventional radiography, computed tomography (CT), and magnetic resonance imaging (MRI) [68]. The choice of initial modality should be guided by available resources. Ultrasonography is a reasonable initial modality; further imaging may be pursued depending on individual patient circumstances and available resources.

•Ultrasonography − Ultrasound is a useful tool to distinguish mycetoma from other subcutaneous masses; the presence of grains may be demonstrated by sharp hyper-reflective echoes [69].

•Conventional radiography − Radiographic imaging is useful for evaluating the extent of soft tissue and bone involvement [70]. Radiographic findings include soft tissue swelling, osteoporosis, and osteolytic lesions (image 1) [71-73]. It is not possible to establish presence of grains with conventional radiography.

•Computed tomography − CT is more sensitive than conventional radiography for assessing early bone involvement and osteoarticular damage. It is not possible to establish presence of grains with CT.

•Magnetic resonance imaging − MRI is useful for assessing the scope of soft tissue involvement early in the course of disease, prior to development of sinus tracts and discharge [68,74]. Presence of the "dot-in-circle sign" on MRI (multiple small, round to oval-shaped hyperintense lesions surrounded by a rim [circle] with a tiny central focus [dot]) correlates with inflammatory granulomata-containing grains, surrounded by fibrous matrix [68,75]. This finding may be seen in eumycetoma or actinomycetoma.

●Findings of bone involvement − Bone involvement usually occurs later in the course of disease. Bone cavity size depends on the grain size, which depends on the etiologic agent. In eumycetoma, cavitary bone lesions tend to be few in number and ≥1 cm in diameter, with well-defined margins. In contrast, cavitary bone lesions due to bacterial pathogens tend to be smaller and more numerous [41,76].

Laboratory evaluation

Histopathology — The histopathologic evaluation should include hematoxylin and eosin as well as periodic acid-Schiff or Gomori methenamine silver staining. Histopathologic findings of eumycetoma consist of a chronic granulomatous reaction with purulent center.

Grains of different morphologies may be observed; characteristics of grains inside the tissue may vary depending on the specific etiology (picture 6 and picture 7). Hyphae (broad, septate, and branching hyphae with large swollen cells at the edge) may be observed within grains or in the absence of grains; hyphae may be hyaline or pigmented. Grain cement (composed of melanoproteins) may or may not be seen; if present, it may be compact or loose [77]. (See 'Microbiology' above.)

Certain characteristics may be helpful for presumptive species identification:

●M. mycetomatis grains are 0.5 to 3 mm, appear rounded, oval, or trilobed, and consist of intertwining hyphae embedded in interstitial brownish cement. Grains may be of filamentous and/or vesicular types; either or both may be observed in the same lesion [78]. A filamentous grain may include brown septate and branched hyphae in the periphery; a vesicular grain may contain unusually large cells that look like vesicles. These findings may be used for presumptive identification but may not be used for definitive diagnosis.

●S. apiospermum species complex grains are eosinophilic with a clear central area, abundant swollen cells, and without cement. Fluorescent antibody reagents have been developed to detect S. apiospermum species complex in tissues, providing a rapid, reliable method for diagnosis [79].

Grain identification and fungal culture

●Obtaining material − FNA is preferred over extrusion of sinus material. Collected material should be sent for grain evaluation (macroscopic and microscopic), fungal culture, and histopathologic evaluation [66]. (See 'General approach' above.)

●Grain evaluation − Grains contain colonies of the causative organism (table 1); they may be observed macroscopically and/or microscopically. In direct microscopic examination, grains are mounted on a slide and crushed under a cover glass. Grains should be examined with 20% potassium hydroxide solution to identify fungal structures (broad, septate, and branching hyphae with large swollen cells at the edge) (picture 8). Gram staining may be useful to demonstrate the presence of bacteria causing actinomycetoma. In some cases, grains are visible only by histopathologic examination. (See 'Histopathology' above.)

Black grains reflect fungal infection, establishing a diagnosis of eumycetoma; M. mycetomatis is the most common cause of black-grain eumycetoma. White to yellow grains may reflect fungal or bacterial infection; S. apiospermum species complex are the most common causes of white-grain eumycetoma. (See 'Microbiology' above.)

●Culture − Grains and tissue from deep aspiration or biopsy must be cultured for definitive species identification. The causative agents of eumycetoma grow as molds with septate hyphae. Culture specimens should be washed with sterile saline solution prior to inoculation onto Sabouraud dextrose agar medium (with and without chloramphenicol and cycloheximide).

To increase yield, tissue samples should be plated without grinding. Two sets of media should be inoculated; one plate should be incubated at 25°C (room temperature) and the other plate should be incubated at 37°C. The plates should be incubated for six to eight weeks, since some causative agents grow relatively slowly. Following successful isolation in culture, standard mycologic or molecular techniques may be used for identification.

Molecular testing — Molecular techniques are reliable for identification of causative agents of eumycetoma; tools include 16S rRNA gene sequencing studies and species-specific polymerase chain reaction for the most prevalent organisms. Molecular tools are especially useful for circumstances in which macroscopic and microscopic features are not sufficient for precise identification, due to absence of distinctive structures. Molecular test results are available in a few hours (whereas culture requires at least a couple weeks) [80]. These tests are costly and not universally available but may be performed in specialized laboratories.

A novel molecular technique consists of rolling circle amplification (RCA), which involves isothermal amplification of circular DNA molecules. This is a rapid and specific tool for diagnosis of black-grain eumycetoma-causative agents (M. fahalii, M. mycetomatis, M. pseudomycetomatis, M. tropicana, T. grisea, F. senegalensis, Falciformispora tompkinsii, and Medicopsis romeroi); it has specificity of 100 percent with no cross reactivity [81]. RCA also has been used for identification of a white-grain eumycetoma agent, Scedosporium boydii [82].

DIFFERENTIAL DIAGNOSIS — Conditions that may present with a triad of tumor (painless firm subcutaneous mass), sinus tracts, and discharge-containing grains (macroscopic or microscopic) include mycetoma (eumycetoma or actinomycetoma) and botryomycosis. Eumycetoma is caused by fungal infection, actinomycetoma is caused by bacterial infection (most commonly nocardia), and botryomycosis is caused by bacterial infection (most commonly S. aureus). Actinomycetoma is more aggressive and destructive than eumycetoma, with earlier bone invasion. The infections may be distinguished based on Gram stain and culture. (See "Botryomycosis" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Skin'.)

Other considerations in the differential diagnosis of eumycetoma depend on the stage of the lesion.

The differential diagnosis of early lesions includes:

●Foreign body granuloma – A foreign body granuloma is a response of biologic material to foreign material in the tissue. The diagnosis may be established radiographically or via biopsy.

●Soft tissue tumor – Soft tissue swelling may reflect a benign soft tissue tumor (such as a lipoma) or a malignant tumor (such as sarcoma, metastatic carcinoma, melanoma, or lymphoma). The diagnosis is established via biopsy. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

●Cystic lesion – A cyst is a closed pocket of tissue that may be filled with fluid, pus, or other material. Epidermoid cysts are the most common cutaneous cysts; the diagnosis is usually based on the clinical appearance of a discrete nodule, often with a central punctum that is freely movable on palpation. (See "Overview of benign lesions of the skin", section on 'Cysts'.)

●Folliculitis – Folliculitis is a superficial infection of the hair follicles with purulent material in the epidermis. The diagnosis of folliculitis is based upon clinical manifestations. (See "Infectious folliculitis".)

The differential diagnosis in the absence of sinus tracts or grains includes:

●Sporotrichosis – Sporotrichosis is a subacute to chronic infection caused by species from the Sporothrix schenckii complex. Infection usually involves cutaneous and subcutaneous tissues but can occasionally occur in other sites. The diagnosis is established via culture. (See "Clinical features and diagnosis of sporotrichosis".)

●Chromoblastomycosis – Chromoblastomycosis is a subcutaneous fungal infection caused by one of several dematiaceous (pigmented) fungi. Examination of skin scrapings with potassium hydroxide or skin biopsy demonstrates characteristic pigmented Medlar bodies, which are thick-walled structures 4 to 12 micrometers in diameter that are globe shaped and copper colored. Fungal culture allows species differentiation.

●Cutaneous leishmaniasis – Cutaneous leishmaniasis is a protozoal infection that produces skin ulcers. The diagnosis requires demonstration of the parasite in a clinical specimen (usually skin) by histology, culture, or molecular analysis via polymerase chain reaction. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

●Mycobacterial infection – Cutaneous tuberculosis, tuberculous lymphadenitis, and atypical mycobacterial infection may present with skin lesions and draining sinus tracts. (See "Cutaneous manifestations of tuberculosis" and "Overview of nontuberculous mycobacterial infections" and "Buruli ulcer (Mycobacterium ulcerans infection)".)

●Elephantiasis – Elephantiasis refers to severe lymphedema that occurs in the setting of filariasis, which is caused by nematodes (roundworms) that inhabit the lymphatics and subcutaneous tissues. The diagnosis is established via antigen testing and/or blood smear examination. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis" and "Lymphatic filariasis: Treatment and prevention".)

●Podoconiosis – Podoconiosis is an inflammatory reaction to mineral particles in certain soils that can result in lymphedema and elephantiasis. Podoconiosis occurs in the tropics at altitudes higher than those at which mosquitoes can transmit filarial infection (a maximum of about 1500 meters, or 4920 feet).

Bone involvement should prompt consideration of:

●Bacterial osteomyelitis – The diagnosis of osteomyelitis is established via isolation of bacteria from a bone biopsy sample together with histologic findings of inflammation and osteonecrosis. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)

●Skeletal tuberculosis – The diagnosis of musculoskeletal tuberculosis is established by microscopy and culture of infected material. (See "Bone and joint tuberculosis".)

●Malignant bone tumor – Bone tumors include osteosarcoma, chondrosarcoma, Ewing sarcoma, and other tumors. The diagnosis is established via histopathology. (See "Bone tumors: Diagnosis and biopsy techniques".)

●Yaws – Yaws is a nonvenereal treponematosis endemic in rural areas among communities living in overcrowded conditions with poor hygiene. It usually occurs in children and affects skin and bones; it is transmitted by direct skin-to-skin, nonsexual contact with infectious lesions. The diagnosis is established via serology. (See "Yaws, bejel, and pinta".)

TREATMENT

General approach — Treatment of eumycetoma requires prolonged antifungal therapy. The optimal role for surgery is uncertain; if pursued, surgery should be performed after at least six months of antifungal therapy. There are no randomized trials to guide treatment; the approach is based on small case reports with limited follow-up.

Antifungal therapy — Treatment consists of azole antifungal therapy, based on reported in-vitro susceptibility data. Agents with inadequate activity include amphotericin, echinocandins, terbinafine, and 5-flucytosine.

The choice of antifungal therapy is guided by grain type. Identification of the causative agent is important to guide the choice of treatment, given variability in antifungal susceptibility among species [80]. However, the choice and duration of antifungal therapy must be tailored to individual patient circumstances, as in vitro susceptibility testing does not always predict the clinical response to therapy.

If differentiation between eumycetoma and actinomycetoma is not possible, we administer initial empiric treatment for actinomycetoma; this condition generally responds more rapidly to treatment. In the absence of clinical improvement after eight weeks of empiric treatment for actinomycetoma, we switch to treatment for eumycetoma. (See "Treatment of nocardiosis", section on 'Mycetoma'.)

Black grain

●Our approach − For treatment of the most frequently observed black-grain eumycetomas (M. mycetomatis, T. grisea, and F. senegalensis), we favor itraconazole (200 mg orally twice daily); the duration should be at least 12 months and depends in part on decisions regarding surgical intervention. (See 'Surgery' below and 'Duration of treatment and follow-up' below.)

Given variable serum levels of itraconazole, serum drug-level monitoring should be performed (if feasible) after steady state has been reached (about two weeks), with goal serum level >1 mcg/mL.

●Alternative agents − For patients with intolerance or whose disease is refractory to itraconazole, acceptable alternatives include voriconazole or posaconazole; disease is considered refractory to itraconazole if there is clinical progression despite at least three months of treatment [83].

Voriconazole and posaconazole have been assessed in a small number of patients with promising results; as with itraconazole, a prolonged duration of treatment is required [83-88]. Dosing is as outlined below. (See 'White to yellow grain' below.)

Clinical data on other agents such as isavuconazole are limited but could be promising given favorable pharmacokinetic characteristics [89,90].

●In vitro susceptibility − In vitro susceptibility of M. mycetomatis is favorable for ketoconazole, itraconazole, voriconazole, posaconazole, and isavuconazole; fluconazole should not be used due to intrinsic resistance [89,91-93]. Similar susceptibility results have been observed with other causative agents of black-grain eumycetoma [90].

Ketoconazole was the mainstay of therapy for many years; however, its use has been restricted by the US Food and Drug Administration in 2013 because of a high rate of adverse effects including hepatotoxicity, QT prolongation, and drug interactions.

●Supporting evidence – Use of itraconazole is supported by a study including 13 patients with M. mycetomatis treated with itraconazole (400 mg daily for three months, followed by 200 mg daily for nine months). The initial clinical response was favorable (as demonstrated by improvement of overlying skin appearance, reduced swelling, diminished discharge, and progressive healing of sinus tracts) but slowed when the dose was reduced [94].

White to yellow grain

●Our approach – For treatment of eumycetoma due to S. apiospermum species complex, we favor voriconazole (loading dose 400 mg orally every 12 hours for the first 24 hours, followed by 200 mg twice daily; the dose may be increased to 300 mg twice daily if needed). The duration consists of at least 12 months, and depends in part on decisions regarding surgical intervention (see 'Surgery' below and 'Duration of treatment and follow-up' below). Given variable serum levels of voriconazole, serum drug level monitoring should be performed (if feasible) after steady state has been reached (about five to seven days) with goal serum level 1 to 5 mcg/mL [95].

●Alternative agents – For patients with intolerance or whose infection is refractory to voriconazole, acceptable alternatives include posaconazole extended-release tablets (300 mg twice daily for the first day, then 300 mg daily) or posaconazole oral suspension (200 mg four times daily or 400 mg twice daily) [83,96-98]

●Supporting evidence – The above approach is supported by studies describing use of voriconazole for treatment of invasive infection, including severe and disseminated disease involving bone and central nervous system, due to S. apiospermum species complex with favorable results (as demonstrated by improvement of overlying skin appearance, reduced swelling, diminished discharge, and progressive healing of sinus tracts) [84,99-103].

Clinical data on treatment of Scedosporium infection are discussed in detail separately. (See "Treatment of Scedosporium and Lomentospora infections".)

Surgery — The optimal role of surgery for management of eumycetoma is uncertain and the indications and techniques for management are not well standardized [104]. If surgery is performed, it should always be in conjunction with antifungal treatment.

●Small, well-demarcated lesions − For patients with small, well-demarcated lesions, in the absence of bone involvement, we favor early surgery in regions with appropriate expertise; in such cases, a wide margin of healthy tissue should be excised [105]. If surgical excision is pursued, at least six months of antifungal therapy should be administered prior to debridement, to enhance encapsulation and reduce the burden of infection, facilitating local excision [94,106]. In addition, antifungal drugs should be administered following surgery for at least 12 months, to reduce the likelihood of recurrence [106,107]. Following excision, primary closure or reconstruction with flaps or grafts is performed.

The above approach is supported by a study including 13 patients with M. mycetomatis treated with itraconazole for 12 months prior to debridement. In all patients the lesions were well localized and easily resected [94]. No postoperative antifungal treatment was administered; after a follow-up period ranging from 18 to 36 months, one patient presented with recurrence.

●Bone involvement − In the setting of bone involvement, definitive management may require amputation [105]. Amputation also may be pursued in cases of severe, progressive disability [105]; in such cases, the goal of amputation should be to prevent further deterioration in quality of life.

Duration of treatment and follow-up — The optimal duration of antimicrobial therapy for treatment of eumycetoma is uncertain and depends on individual circumstances. In general, at least 12 months of therapy is appropriate; treatment may be required for two years or more. Bone involvement indicates a poor prognosis and requires a longer course of therapy. Hepatic enzyme monitoring should be performed monthly during azole therapy.

Treatment should be continued for at least three months after a clinical and radiographic cure is achieved. Clinical signs of improvement include reduction in swelling, decreasing purulent discharge, closing of sinus tracts, reduction in pain, and improvement of mobility. Radiographic signs of improvement include resolution of soft tissue involvement and improvement in bone lesions; ultrasonographic signs of improvement include disappearance of grains and cavities. Patients should be followed for at least two years after discontinuation of antimicrobial therapy before declaring a cure [23]. We do not perform biopsy to assess for cure.

OUTCOMES — Relapse is common and is attributable to several factors. In one study that included 1013 patients in Sudan who had eumycetoma due to M. mycetomatis and who underwent surgical excision, relapse occurred in 27 percent of cases. Risk factors for relapse included disease duration ≥10 years, extrapedal involvement, previous surgical excision, and family history of mycetoma [108]. In a subsequent study including more than 500 patients in Sudan with eumycetoma who underwent excision, the recurrence rate at 18-month follow-up was 5.5 percent; risk factors included bone involvement, recurrent disease, and lesion size ≥5 cm [109].

PREVENTION — Use of protective equipment including shoes and gloves should be promoted in the setting of contact with soil whenever possible. In addition, health care professionals working in endemic areas must be educated to recognize and treat eumycetoma promptly before progression to advanced disease.

SUMMARY AND RECOMMENDATIONS

●Definition − Mycetoma is a chronic skin and soft tissue infection resulting in a mass, sinus formation, and discharge-containing grains. Surrounding tissues can be involved by contiguous spread. Mycetoma can be caused by fungi (eumycetoma) or bacteria (actinomycetoma, most commonly actinomyces, streptomyces, or Nocardia species). (See 'Introduction' above.)

●Epidemiology − Most cases of eumycetoma occur in resource-limited countries in tropical and subtropical regions, although cases have been reported worldwide. Eumycetoma most frequently involves the feet, followed by legs and hands, where exposure to contaminated soil occurs most commonly. (See 'Epidemiology' above and 'Clinical manifestations' above.)

●Pathogenesis − Eumycetoma begins with traumatic inoculation of the organism into cutaneous and/or subcutaneous tissues. Trauma may be minor (due to thorns, splinters, or other objects), and patients may not recall a specific injury. Grains (colonies of infecting organisms) are formed in infected tissues. The grains are partially broken down via a neutrophil-mediated inflammatory reaction; their remains perpetuate an inflammatory response. (See 'Pathogenesis' above.)

●Microbiology − Organisms capable of causing eumycetoma are distributed worldwide and include at least 44 hyaline and pigmented species of molds (table 1 and figure 1). (See 'Microbiology' above.)

●Diagnosis – A clinical diagnosis of mycetoma may be established in patients with the characteristic triad of tumor, sinus tracts, and discharge-containing grains. The evaluation usually consists of ultrasonography (demonstrating grains and/or cavities) followed by fine needle aspiration. A definitive diagnosis of eumycetoma may be established by histopathologic evaluation demonstrating hyphae; culture is required for species identification. (See 'General approach' above and 'Laboratory evaluation' above.)

●Grain identification − Grains may be observed macroscopically and/or microscopically; in some cases, they are visible only by histopathologic examination. Black grains reflect fungal infection, establishing a diagnosis of eumycetoma; white to yellow grains may reflect fungal or bacterial infection. (See 'Grain identification and fungal culture' above.)

●Treatment − Treatment of eumycetoma requires prolonged antifungal therapy and surgery in some cases.

•Antifungal therapy − The choice of antifungal therapy is guided by grain type. Identification of the causative agent is important, given variability in antifungal susceptibility between species. However, the choice and duration of antifungal therapy must be tailored to individual patient circumstances, as in vitro susceptibility testing does not always predict the clinical response to therapy. (See 'Antifungal therapy' above.)  

-Selection − For treatment of black-grain eumycetomas caused by Madurella mycetomatis, Trematosphaeria grisea, or Falciformispora senegalensis, we suggest itraconazole rather than other azoles (Grade 2C).

For treatment of white to yellow grain eumycetomas caused by Scedosporium apiospermum species complex, we suggest voriconazole rather than other azoles (Grade 2C). (See 'Antifungal therapy' above.)

-Duration − The duration of antifungal treatment is at least 12 months, tailored to individual patient circumstances.

Treatment should be continued for at least three months after a clinical and radiographic cure is achieved. (See 'Duration of treatment and follow-up' above.)

•Surgery − For patients with small, well-demarcated lesions in the absence of bone involvement, we suggest early surgical excision in regions with appropriate expertise (Grade 2C). In such cases, we administer antifungal therapy for at least six months prior to debridement and at least 12 months afterwards.

In the setting of bone involvement, definitive management may require amputation. (See 'Surgery' above.)