AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Mycetoma is a chronic, granulomatous disease of the skin and subcutaneous tissue, which sometimes involves muscle, bones, and neighboring organs. It is characterized by tumefaction, abscess formation, and fistulae. It typically affects the lower extremities, but it can occur in almost any region of the body. Mycetoma predominately occurs in farm workers, but it can also occur in the general population.

Gill first described the disease in the Madura district of India in 1842, hence the term Madura foot. In 1860, Carter named the condition mycetoma, describing its fungal etiology. In 1813, Pinoy described the mycetoma produced by aerobic bacteria that belong to the actinomycete group and classified mycetomas as those produced by true fungi (eumycetoma) versus those due to aerobic bacteria (actinomycetoma). Both types have similar clinical findings.

Pathophysiology

Mycetoma is produced by the introduction of microorganisms (bacteria or fungi) via localized trauma of the skin with thorns, wood splinters, or implantation with solid objects. Clinically, the disease begins as small, firm nodules that can persist (mini-mycetomas) or evolve to form extensive suppurative plaques measuring up to 20 cm in diameter. Eumycetomas tend to be more localized than actinomycetomas.

In experimentally induced Nocardia brasiliensis actinomycetomas in mice, production of granules (or "grains") containing the bacterium can be observed 15 days after inoculation. The grains are surrounded by polymorphonuclear cells (PMNs), lymphocytes, plasma cells, and histiocytes. Murine infection can evolve into a chronic disease similar to the clinical manifestations observed in humans. Severe inflammation and deformity, abscesses, ulcers, and fistulae are present 28 days after infection.

The host immune response in humans and mice involves the production of high levels of anti–N brasiliensis immunoglobulin G antibodies. Quantitation of these antibodies is important for diagnosis. Immunoglobulin M anti–N brasiliensis antibodies can protect mice from an experimental infection. Activation of cellular immunity and production of cytokines are involved in resistance and elimination of the N brasiliensis bacterial cells.

Frequency

United States

Mycetoma occasionally occurs in the United States, particularly in the South.

International

Mycetoma is endemic around the Tropic of Cancer, 15° south and 30° north of the equator, in tropical, subtropical, and temperate regions. Mexico, Venezuela, Sudan, India, Pakistan, Senegal, and Somalia have the highest incidences of this disease worldwide. The United States, Asia, and other Latin American countries have reported cases less frequently.

The most common agents isolated in African countries are Madurella mycetomatis, Streptomyces somaliensis, and Actinomadura pelletieri. In Mexico, which shares common climatic conditions with the African countries, most of the cases are found in rural areas. In Mexico, 98% of cases of mycetoma are caused by actinomycetes, mainly N brasiliensis (86%) and Actinomadura madurae (about 8%). In another high frequency area, India, 65% of cases are produced by actinomycetes and the rest by eumycetes, mostly M mycetomatis.

Worldwide, approximately 60% of cases of mycetomas are of actinomycotic origin.

Mortality/Morbidity

Mycetoma is usually painless; individuals who are affected seek medical attention mainly because of the tumefaction and draining sinuses. In the rare cases affecting the thorax or the head, mycetoma can be fatal because of the spread of microorganisms to adjacent organs. Rarely, the disease can spread by hematogenous dissemination (Nocardia asteroides and N brasiliensis).

Sex

Mycetoma is more common in men than in women. The male-to-female ratio is 3:1.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Mycetoma occurs most commonly in people who work in rural areas where they are exposed to acacia trees or cactus thorns containing the etiologic agents that normally live as saprobes. However, the disease has also been found in individuals who work in the city in various occupations.
• If left untreated, mycetoma can affect the underlying bones, joints, or adjacent organs.

Physical

• Examination typically reveals painless tumefaction of the affected area.
• The skin is usually darker and firmer than the surrounding areas.
• Nodules, abscesses, and fistulae draining a clear viscous or purulent exudate can be observed.
• Granules of the microorganisms may occasionally be seen with the naked eye, as in the case of mycetoma caused by A madurae and M mycetomatis among others.
• The most common anatomical locations affected by this disease are the upper and lower limbs, particularly the feet and the lower legs. In Mexico, the next most commonly affected site is the thoracic area, but this varies from country to country. Rarely, mycetoma can also be observed on the buttocks, the groin area, the head, and the neck.

Causes

Eumycetomas can be produced by a variety of fungi (see Table 1); however actinomycetomas are mainly produced by bacteria of 4 genera: Nocardia, Actinomadura, Streptomyces, and Nocardiopsis (see Table 2), the last of which is rarely found.

Table 1. Fungi Causing Mycetoma

Table 2. Microorganisms Causing Actinomycetomas in Humans

DIFFERENTIALS

Section 4 of 11  

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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
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Other Problems to be Considered

Botryomycosis
Other deep fungal infections
Osteomyelitis
Bone and soft tissue tumors

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The first important goal is to differentiate between eumycetoma and actinomycotic mycetoma because treatment is completely different. The most useful procedures for establishing the diagnosis of mycetoma are direct examination with potassium hydroxide (KOH), biopsy, and microbiological cultures.
• • Differentiation is accomplished by microscopic examination of exudate from the draining sinuses. Actinomycetes occur with granules of about 100 µm in diameter, with delicate, branched filaments measuring about 1 µm in diameter. Fungal grains are observed as a mass of hyphae embedded in intercellular cement, and the filaments are wider than 1 µm.
  • Observing the size of the filaments and the color of the granules is important because these characteristics are helpful for initial presumptive identification of the etiologic agent.
• Culture of the lesion is performed by collection of the abscess or the fistula secretion or by tissue biopsy. In both cases, the samples are cultured in media such as Sabouraud agar or mycobiotic agar to isolate fungi and/or blood agar to isolate bacteria. The etiologic agents are identified according to their macroscopic and microscopic features.
• Biochemical tests are particularly useful to identify actinomycetes, although a more conclusive identification is performed by sequencing analysis of the small ribosomal subunit gene or sequencing of conserved genes such as HSP65.
• An enzyme-linked immunosorbent assay (ELISA) to determine anti–N brasiliensis antibodies is used for diagnosis and to assess response to medical treatment.

Imaging Studies

• Radiologic tests (bone radiographs) should be performed if underlying bony involvement is suspected.

Other Tests

• Immunologic tests
• • Several immunologic assays using culture filtrate or cytoplasmic antigens of mycetoma agents have been developed to detect antibodies. In the case of N brasiliensis, it has been observed by Western blot that the humoral response is directed against 3 proteins of 24, 26, and 61 kd of a cellular extract. These proteins were isolated and purified, and the 24- and 26-kd proteins were used to develop an ELISA to detect antibodies against N brasiliensis. A correlation between antibody titers and clinical condition of the patients was observed. In patients with active disease, the titers were high. In patients with cured lesions, the optical density (OD) in the ELISA test was below the cut-off point, with similar results to those obtained with negative controls. To date, the use of a skin antigen for diagnosis has been of little help because of the cross-reactivity with other bacterial infections, such as tuberculosis or leprosy.
  • Regarding the eumycotic mycetoma infections, immunodiffusion tests have been used to detect antibodies. In the case of mycetoma caused by M mycetomatis, an immunodominant protein has been described to induce specific antibodies, which are useful for the identification and prognosis of M mycetomatis mycetoma. A good animal model for studying eumycotic mycetoma has not yet been developed.

Histologic Findings

The histopathologic picture reveals a granulomatous inflammation with abscess formation. A central zone exists where polymorphonuclear cells are abundant and granules or grains are found. This central zone is surrounded by lymphocytes, plasma cells, histiocytes, and fibroblasts. The actinomycetes are seen by staining with hematoxylin and eosin (H&E), Gram, Gridley, and Grocott stains; the eumycetes are more easily observed with H&E, periodic acid-Schiff (PAS), and Grocott/methenamine-silver stains.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Eumycetoma
• • Treatment for eumycetoma is generally less successful than for actinomycetoma. In adults weighing 70 kg, ketoconazole 400 mg daily, itraconazole 300 mg daily, and intravenous amphotericin B 50 mg daily, have been used with some success in cases of eumycetoma. Isolated cases of successful treatment with voriconazole and posaconazole have been reported. Therapy is suggested for 1-2 years (or greater) for complete eradication, unless adverse effects warrant cessation of medication.
  • In 2 cases, the authors have used a combination of itraconazole and terbinafine resulting in the remission of the disease. Surgical treatment remains a viable therapy for mycetoma caused by fungi.
• Actinomycetoma
• • The current treatment of actinomycetoma is trimethoprim-sulfamethoxazole 7.5-40 mg/kg daily in 3 oral doses for several months or years. In certain anatomical sites (eg, thorax, head), extensive lesions, or cases recalcitrant to the above therapy, amikacin 15 mg/kg intramuscularly daily should be added. Every 2 or 3 weeks, a periodic audiometric and creatine clearance analysis must be performed. This treatment is maintained for 5-15 weeks and, in some cases for a longer period of time, depending on the clinical response and renal and auditory adverse effects.
  • Netilmicin can be used in cases resistant to amikacin. Other antimicrobials, such as minocycline, amoxicillin-clavulanic acid, streptomycin, imipenem, and rifampin, have also been used with variable success. An oxazolidinone, linezolid, has been proven to be active in vitro, in vivo, and in clinical nocardial infections. Other experimental oxazolidinone drugs such as DA-7867 and DA-7218 are active in vitro and in experimental models of N brasiliensis infection, although they have not been used in humans.

Surgical Care

• In eumycetoma, surgical treatment is a therapeutic option if the patient's condition has not responded to medical treatment alone. In these cases, both modalities are typically used.
• Surgical treatment, including amputation, for actinomycetoma is seldom indicated.

MEDICATION

Section 7 of 11  

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• References

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the disease.

Drug Category: Antifungals

Ketoconazole, itraconazole, amphotericin B, and terbinafine are most commonly used to treat mycetoma. When systemic agents are administered, monitoring patients for adverse effects and complications common to the drug is important. Therapy is suggested for 1-2 years (or greater) for complete eradication, unless adverse effects warrant cessation of medication.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• Actinomycetomas generally respond well to the treatment previously mentioned (see Medication) in 90% of cases. In cases where the bacteria have become resistant to the above therapy, antibiotic susceptibility testing should be performed to select the best antimicrobial agent or agents to be used.
• Eumycetoma tends to be a more chronic disease, and success of medical therapy is observed in only about 40% of cases. If the response is partial or negative to medical treatment, surgery of the affected area should be performed, and antifungal drugs continued until complete remission of the disease.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Special Concerns

• When prescribing imidazole antifungals, considering interactions with other medications (eg, rifampin, cyclosporin A, warfarin) that interact with cytochrome P450 is important. Azole administration is contraindicated during pregnancy.
• Aminoglycosides can induce ototoxicity and renal damage; therefore, the administration of these drugs must include a careful evaluation of auditory and kidney function during treatment.
• Sulfonamides can produce gastritis, photosensitivity, and a skin eruption that can sometimes be severe (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). Hematologic adverse effects, including methemoglobinemia, can develop as adverse reactions to these drugs.
• The main adverse effect of amphotericin B is renal impairment that can lead to permanent kidney damage. Other adverse reactions include ECG changes, hypokalemia, anemia, thrombocytopenia, and leukopenia.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Actinomycetoma of the foot (left) and arm (center) caused by Nocardia brasiliensis. Multiple nodules and fistulae are present. Microscopic examination of the pus (right). The granules are multilobulated and are surrounded by abundant clubs.
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Media type:  Photo

Media file 2:  Eumycetoma. Mycetoma of the hand (left). Microscopic features of a Madurella mycetomatis grain are observed (center). Notice the presence of brownish hyphae and intercellular cement (hematoxylin and eosin stain). Macrocolony of another eumycotic agent, Pseudallescheria boydii (right).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. Apr 2006;19(2):259-82. [Medline].
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• Fuentes A, Arenas R, Reyes M, Fernández RF, Zacarías R. [Actinomycetoma and Nocardia sp. Report of five cases treated with imipenem or imipenem plus amikacin]. Gac Med Mex. May-Jun 2006;142(3):247-52. [Medline].
• Hay RJ, Mahgoub ES, Leon G, al-Sogair S, Welsh O. Mycetoma. J Med Vet Mycol. 1992;30 Suppl 1:41-9. [Medline].
• Kashima M, Kano R, Mikami Y, Takahama H, Ito M, Hasegawa A, et al. A successfully treated case of mycetoma due to Nocardia veterana. Br J Dermatol. Jun 2005;152(6):1349-52. [Medline].
• Lacroix C, de Kerviler E, Morel P, Derouin F, Feuilhade de Chavin M. Madurella mycetomatis mycetoma treated successfully with oral voriconazole. Br J Dermatol. May 2005;152(5):1067-8. [Medline].
• López Martínez R, Méndez Tovar LJ, Lavalle P, Welsh O, Saúl A, Macotela Ruíz E. [Epidemiology of mycetoma in Mexico: study of 2105 cases]. Gac Med Mex. Jul-Aug 1992;128(4):477-81. [Medline].
• Mahgoub ES, Murray IG. Mycetoma. London, England: William Heinemann; 1973:76-115.
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• N'diaye B, Dieng MT, Perez A, Stockmeyer M, Bakshi R. Clinical efficacy and safety of oral terbinafine in fungal mycetoma. Int J Dermatol. Feb 2006;45(2):154-7. [Medline].
• Negroni R, Tobón A, Bustamante B, Shikanai-Yasuda MA, Patino H, Restrepo A. Posaconazole treatment of refractory eumycetoma and chromoblastomycosis. Rev Inst Med Trop Sao Paulo. Nov-Dec 2005;47(6):339-46. [Medline].
• Rodríguez-Nava V, Couble A, Molinard C, Sandoval H, Boiron P, Laurent F. Nocardia mexicana sp. nov., a new pathogen isolated from human mycetomas. J Clin Microbiol. Oct 2004;42(10):4530-5. [Medline].
• Salinas-Carmona MC, Pérez-Rivera I. Humoral immunity through immunoglobulin M protects mice from an experimental actinomycetoma infection by Nocardia brasiliensis. Infect Immun. Oct 2004;72(10):5597-604. [Medline].
• Salinas-Carmona MC, Welsh O, Casillas SM. Enzyme-linked immunosorbent assay for serological diagnosis of Nocardia brasiliensis and clinical correlation with mycetoma infections. J Clin Microbiol. Nov 1993;31(11):2901-6. [Medline].
• van de Sande WW, Janse DJ, Hira V, Goedhart H, van der Zee R, Ahmed AO, et al. Translationally controlled tumor protein from Madurella mycetomatis, a marker for tumorous mycetoma progression. J Immunol. Aug 1 2006;177(3):1997-2005. [Medline].
• Vera-Cabrera L, Gonzalez E, Rendon A, Ocampo-Candiani J, Welsh O, Velazquez-Moreno VM, et al. In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis. Antimicrob Agents Chemother. Sep 2006;50(9):3170-2. [Medline].
• Vera-Cabrera L, Salinas-Carmona MC, Welsh O, Rodriguez MA. Isolation and purification of two immunodominant antigens from Nocardia brasiliensis. J Clin Microbiol. May 1992;30(5):1183-8. [Medline].
• Welsh O. Mycetoma. Current concepts in treatment. Int J Dermatol. Jun 1991;30(6):387-98. [Medline].
• Welsh O, Sauceda E, Gonzalez J, Ocampo J. Amikacin alone and in combination with trimethoprim-sulfamethoxazole in the treatment of actinomycotic mycetoma. J Am Acad Dermatol. Sep 1987;17(3):443-8. [Medline].
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Article Last Updated: Feb 22, 2007