Mycetoma

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Background

Mycetoma is a chronic infection of skin and subcutaneous tissue. The condition was first described in the mid-1800s and was initially named Madura foot, after the region of Madura in India where the disease was first identified.

Mycetoma infection can be caused by fungi or bacteria. When caused by fungi, it is referred to as mycotic mycetoma or eumycetoma. When it is caused by bacteria, it usually involves infection by the actinomycetes group; such cases are called actinomycotic mycetoma or actinomycetoma.[1] Involvement of the lower extremities is common, and the disease presentation, whether caused by fungi or bacteria, is quite similar.

Mycetoma infection typically results in a granulomatous inflammatory response in the deep dermis and subcutaneous tissue, which can extend to the underlying bone. Mycetoma is characterized by the formation of grains, which contain aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses.[2] The characteristic color of the grains can assist in the identification of the specific etiologic agent.

Mycetoma due to actinomycetes should be differentiated from actinomycosis, which is an endogenous suppurative infection caused by Actinomyces israelii, other species of Actinomyces, or related bacteria, typically affecting the cervical-facial, thoracic, and pelvic sites (the latter is usually associated with the use of intrauterine devices). The branching bacteria that cause actinomycosis are non–acid-fast anaerobic or microaerophilic bacteria. These bacteria are smaller than 1 µm in diameter, smaller than eumycotic agents. Alternatively, the agents that cause actinomycetoma are always aerobic and are sometimes weakly acid-fast.

More than 20 species of fungi and bacteria can cause mycetoma. Nocardia species, especially Nocardia brasiliensis, is the most commonly implicated actinomycetes.[3]

The ratio of mycetoma cases caused by bacteria (actinomycetoma) to those caused by true fungi (eumycetoma) in Mexico was 92:8.[4]

Pathophysiology

The body parts affected most commonly in persons with mycetoma include the foot or lower leg, with infection of the dorsal aspect of the forefoot being typical. The hand is the next most common location; however, mycetoma lesions can occur anywhere on the body. Lesions on the chest and back are frequently caused by Nocardia species, whereas lesions on the head and neck are usually caused by Streptomyces somaliensis.

The causative organism enters through sites of local trauma (eg, cut on the hand, thorn or foot splinter). Contaminated soil seems to be the real culprit, even when a splinter or thorn is implicated. A neutrophilic response initially occurs, which may be followed by a granulomatous reaction. Spread occurs through skin facial planes and can involve the bone. Hematogenous or lymphatic spread is uncommon.

Human-to-human or animal-to-human transmission has not been described for eumycetoma, but nosocomial transmission of Nocardia farcinica, one of the agents of actinomycetoma in postoperative surgical site infections, has been reported.[5]

Epidemiology

Mycetoma is endemic in Africa, from Sudan and Somalia through Mauritania and Senegal. Other endemic countries include Mexico and India. Mycetoma can also be found in natives of areas of Central and South America and the Middle or Far East between latitudes 15°S and 30°N.[6]

Eumycetoma is more common in areas where the average rainfall is scarce (ie, < 350 mm), whereas actinomycetoma tends to appear in areas with abundant rainfall (ie, >600 mm)[7] and has been described in Southeast Asia.[8]

In Sudanese hospitals, at least 300-400 patients are diagnosed with mycetoma every year.

Mycetoma is rare in the United States. Some cases are acquired during international travel, but cases acquired on US soil have also been reported.[9]

In general, traumatic inoculation of fungal elements into the skin or subcutaneous tissue by a thorn or splinter typically occur in those who walk bare-footed (eg, farmers, field workers), especially in developing countries.

Among the fungal pathogens responsible for mycetoma, Madurella mycetomatis is the most common pathogen described in Africa. Madurella grisea is the most common etiologic pathogen in South America. Pseudallescheria boydii (Scedosporium apiospermum) is the most common etiologic agent in the United States.

Mortality/Morbidity

Mycetoma causes disfigurement but is rarely fatal in the absence of skull involvement. The lesions are painless and slowly progressive; however, secondary bacterial infection or bone expansion may cause pain. When secondary bacterial infection occurs, Staphylococcus aureus is the most common etiologic agent.[10] In advanced cases, deformities or ankylosis and their corresponding disabilities can appear. Patients who are immunocompromised or who have undergone transplantation can develop invasive infection.



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Mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.



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Frontal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.

Race

Mycetoma has no apparent racial predilection.

Sex

Mycetoma has a male-to-female ratio of 3:1 to 5:1

Age

Mycetoma is most common in persons aged 20-50 years, with a mean of 34 years.

History

The classic clinical triad of mycetoma is tumor or soft tissue swelling, sinus tracts, and characteristic macroscopic grains. The grains typically represent aggregates of the infecting organisms. The earliest sign is often painless subcutaneous swelling. Some patients may give a history of a penetrating injury at the site of involvement.

Several years later, a painless subcutaneous nodule is observed. After some years, massive swelling of the area occurs, with induration, skin rupture, and sinus tract formation.

As the infection spreads to contiguous body parts, old sinuses close and new ones open.

Nearly 20% of patients with mycetoma experience associated pain, usually due to secondary bacterial infection or, less commonly, bone invasion.

Constitutional symptoms and signs of mycetoma are rare.

Patients may report a deep itching sensation.

Physical

Irrespective of the causal agent, the appearance of the mycetoma lesion is consistent, as follows:

In general, eumycetoma is more circumscribed and progresses slower than actinomycetoma.

Regional lymphadenopathy is unusual; when it does occur, it is due to one of the following:

Lymphatic obstruction and fibrosis can cause lymphedema and erythema.

Pulmonary mycetoma has been found to develop and progress more rapidly in individuals infected with HIV.

Causes

Mycetoma occurs most often in farmers, shepherds, Bedouins, nomads, and people living in rural areas.

Frequent exposure to penetrating wounds by thorns or splinters is a risk factor, especially in combination with contaminated soil material.

Actinomycetoma can be caused by the following:

Eumycetoma is mainly caused by P boydii (S apiospermum), Madurella mycetomatis, or M grisea.[11] Madurella has been identified in cattle dung in rural East Africa.[12]

​The color of the grains is sometimes helpful in pinpointing the exact etiologic agent. For example, the grains of M mycetomatis or M grisea ​are typically black, while those of P boydii ​and several actinomycetes are usually faint yellowish or white.

Approach Considerations

Currently, multiple diagnostic tools are used to determine the extent of infections and to identify the causative agents of mycetoma. These include various imaging, cytological, histopathological, serological, and culture techniques; phenotypic characterization; and molecular diagnostics.[13]

Imaging Studies

Bone radiography

Only 3% of patients with mycetoma have normal radiographs.[14]

Once mycetoma has invaded the bone, the following changes may be observed:

Bone involvement has been radiographically classified, as follows:

MRI

MRI helps with the differential diagnosis and the assessment of the degree of bone and soft-tissue involvement.[15] The dot-in-circle sign is an easy-to-recognize and highly specific MRI sign of mycetoma.[16, 17]



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MRI coronal section of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. ....



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MRI with coronal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years....

Ultrasonography

Single or multiple thick-walled cavities with hyperreflective echoes and no acoustic enhancement are always observed with mycetoma, whereas these features are not demonstrated in nonmycetoma swellings.

In eumycetoma, the hyperreflective echoes are sharp, corresponding to the grains in the lesion.

In actinomycetoma, the hyperreflective echoes are fine and closely aggregated and commonly settle at the bottom of the cavities.

CT scanning

This modality provides a better detail of changes than conventional radiography.

Procedures

Perform a deep wedge biopsy or puncture and fine-needle aspiration to obtain a grain sample. The aspirated material is processed to form cell blocks and further studied for routine tissue histopathological examination.[18] Fine-needle aspiration cytology allows differentiating actinomycetoma from eumycetoma.[19]

Histologic Findings

Grains are surrounded closely and sometimes infiltrated by neutrophils and can be easily seen on histologic sections. In biopsy samples, staining with Gram stain (actinomycetoma) or Gomori methenamine silver or periodic acid-Schiff stains (eumycetoma) could help in identifying the causal agent. For mycetomas in which causative infectious agents cannot be isolated, histology may prove beneficial by avoiding inadvertent use of combined antifungal and antimicrobial agents so that a correct therapeutic modality can be decided.[20]

Staging

Radiographic staging of bone involvement can be found in Imaging Studies.

Lab Studies

Staining

Hematoxylin-eosin staining of a biopsy sample allows for detection of mycetoma grains.

Process hematoxylin-eosin and May-Grünwald-Giemsa staining of a cytologic smear of a sample obtained via fine-needle aspiration. Mycetoma grains can be distinguished from artifacts and other organisms by the intimate relationship between the grain and neutrophils. The appearance of the grains is as follows:

The causal agent of each type of mycetoma can be visualized better with the following:

Evaluation of the characteristics of the associated granules suggests an initial differential diagnosis, as follows:

Culture

Culture the grains obtained from a deep wedge biopsy or a sample obtained via puncture and fine-needle aspiration. The primary isolation media used should be Löwenstein-Jensen for actinomycetoma or blood agar for eumycetoma.

Superficial samples of the draining sinuses are inadequate for culture because of frequent contamination with bacteria.

Serology

Serologic diagnosis is available in a few centers and can be helpful in some cases for diagnosis or follow-up care during medical treatment. Antibodies can be determined via (1) immunodiffusion, (2) counterimmunoelectrophoresis, (3) enzyme-linked immunosorbent assay, or (4) Western blot.

Medical Care

In the treatment of mycetoma, antibiotic or antifungal therapy should be attempted first and may need to be combined with surgery,[2] especially for eumycetoma lesions in the extremities.[21]

External beam radiotherapy in doses ranging from 3.5-14 Gy has been considered successful treatment in a few selected cases.[22]

Surgical Care

Surgery is recommended for localized mycetoma lesions that can be excised completely without residual disability. Surgical reduction of large lesions can improve the patient's response to medical treatment.[23] However, partial surgical resection without subsequent use of appropriate antimicrobial or antifungal agents is prone to failure.

Consultations

Consultation with specialists in infectious disease or tropical medicine is advised in areas of the world where mycetoma is unfamiliar.

Medication Summary

Treatment for mycetoma is generally a combination of medical and surgical therapy. Medical therapy alone may be sufficient for actinomycetoma, but surgery is generally needed for eumycetoma. Medical therapy is often prolonged, lasting for months to years.

Actinomycetoma is a bacterial infection that can respond to antibiotics[24] if treatment is administered early in the course of the disease.[25] A combination of 2 drugs in 5-week cycles is used. If needed, the cycles can be repeated once or twice. The following agents have been used in combination: trimethoprim-sulfamethoxazole (TMP-SMZ), dapsone (diaminodiphenylsulfone), and streptomycin sulfate. Amikacin can be substituted for streptomycin but is usually kept as a second-line drug because of its cost.

The combination of amikacin with cotrimoxazole (so-called Welsh regimen) is increasingly favored by many. Adding rifampin to the Welsh regimen (Modified Welsh regimen) allows for remissions without recurrence.[26] However, a case of actinomycetoma was reported as still improving after 5 years of continued treatment with cotrimoxazole only.[27]

In one case report, a patient required salvage therapy with amikacin and imipenem for 6 months.[28] An effective and convenient regimen combining a short course of intravenous gentamicin with a 6-month oral course of cotrimoxazole and doxycycline has been described.[29, 30]

Although eumycetoma may respond partially to antifungal agents, surgical removal is usually done first.[31] The most successful treatment option for eumycetomas is itraconazole 200 mg twice daily. This triazole antifungal is considered the criterion standard for eumycetomas. The less-expensive ketoconazole is no longer favored owing to side effects and multiple drug interactions.[32] ​ Fluconazole is also discouraged because of intrinsic resistance.[33]

P boydii (S apiospermum) mycetoma should be treated primarily with voriconazole, although it may also respond to itraconazole. Other agents that cause eumycetoma may respond intermittently to itraconazole or amphotericin B.

Voriconazole is the drug of choice for invasive infections caused by agents of eumycetoma in immunocompromised patients.

Posaconazole is highly active in vitro against Madurella mycetomatis, but terbinafine is only moderately active. Since posaconazole has an excellent safety profile, it might provide an important alternative in mycetoma therapy.[34]

Madurella mycetomatis is not susceptible to the echinocandins.[35]

Doxycycline (Bio-Tab, Doryx, Doxy, Periostat, Vibramycin, Vibra-Tabs)

Clinical Context:  Drug of choice. Broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. Almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Trimethoprim-sulfamethoxazole (Bactrim DS, Septra)

Clinical Context:  DOC; inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Should be used continuously in combination with another antimicrobial for 5 wk. Cycle may be repeated prn.

Amikacin (Amikin)

Clinical Context:  Irreversibly binds to 30S subunit of bacterial ribosomes, blocks recognition step in protein synthesis, and causes growth inhibition.

Should be given continuously for 3 wk. Although somewhat expensive, it usually is active against the bacteria causing actinomycetoma. Use the patient's IBW for dosage calculation.

Dapsone (Avlosulfon)

Clinical Context:  Bactericidal and bacteriostatic against mycobacteria. Mechanism of action is similar to sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Lowest-cost regimen. Change to TMP-SMZ if no response occurs after 1 mo.

Rifampin (Rimactane, Rifadin)

Clinical Context:  For use in combination with at least 1 other agent. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.

Imipenem and cilastatin (Primaxin)

Clinical Context:  For treatment of multiple-organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity.

Gentamicin (Garamycin)

Clinical Context:  Aminoglycoside antibiotic for gram-negative coverage bacteria, including Pseudomonas species. Synergistic with beta-lactamase against enterococci. Interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits. Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution, as well as body space into which agent needs to distribute. Gentamicin may be given IV/IM. Each regimen must be followed by at least trough level drawn on third or fourth dose, 0.5 h before dosing; may draw peak level 0.5 h after 30-min infusion.

Class Summary

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

Ketoconazole (Nizoral)

Clinical Context:  Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

Itraconazole (Sporanox)

Clinical Context:  Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Amphotericin B (Fungizone)

Clinical Context:  Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.

Conventional formulation (complexed with deoxycholate) has a poor tolerability profile. Liposomal amphotericin B incorporates the drug into small unilamellar liposomes; this formulation retains the antifungal activity with less hypokalemia, anemia and infusion reactions, and far less nephrotoxicity than the conventional formulation.

Although the acquisition cost of liposomal amphotericin B is considerably higher than that of the conventional formulation, when adverse effects are considered, the calculated total costs of treatment for fungal infections are not clearly different.

Voriconazole (VFEND)

Clinical Context:  Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or S apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Class Summary

In combination with surgical therapy, antifungal agents may help to attain partial response in cases of eumycetoma.

Further Outpatient Care

Patients with mycetoma should receive maintained medical treatment and follow-up care for several months to years.

Prevention

There is currently no vaccine.

Educate patients to avoid activities that expose them to agents of mycetoma. Instruct patients to avoid carrying sticks and thorny branches that have had contact with soil, especially if contaminated with cattle dung.[12] ​ Footwear and protective clothing in at-risk populations, especially in developing countries, is also recommended.

The glycolytic enzyme fructose-bisphosphate aldolase (FBA) is expressed on the hyphae present in the mycetoma grain. FBA antibody levels were found to be significantly higher in eumycetoma patient sera when compared with healthy Sudanese controls. Therefore, FBA might be useful as candidate antigen for a future vaccine against mycetoma.[36]

Complications

Complications of mycetoma result mainly from toxicity due to prolonged administration of antimicrobial or antifungal drugs.

Disfigurement of the affected body parts may be a consequence of delayed treatment.

Amputation may result from neglected chronic infections.

Secondary bacterial infections can progress to full-blown bacteremia or septicemia, resulting in death.[2]

Prognosis

Mycetoma carries a good prognosis if the disease is promptly diagnosed and treated. Although mycetoma carries a low risk of mortality, amputations or ankylosis can lessen the quality of life.[37]

In late stages of mycetoma, the treatment response is limited.

Author

Folusakin O Ayoade, MD, Clinical Fellow, Division of Infectious Diseases, LSU Health Science Center

Disclosure: Nothing to disclose.

Coauthor(s)

Mohammad J Alam, MD, Assistant Professor of Medicine, Departments of Internal Medicine, Infectious Disease, and Emergency Medicine, University Health, Louisiana State University School of Medicine in Shreveport; Affiliate Staff Physician, Department of Internal Medicine (Infectious Disease), Schumpert Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Program Director of Infectious Disease Fellowship, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Basilio J Anía, MD, Associate Professor of Infectious Diseases, Universidad de Las Palmas de Gran Canaria; Consultant in Internal Medicine, Hospital Universitario Dr. Negrín, Spain

Disclosure: Nothing to disclose.

Larry I Lutwick, MD, Professor of Medicine, State University of New York Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus

Disclosure: Nothing to disclose.

Margarita Asenjo, MD, Associate Professor, Department of Radiology, Medical School of the University of Las Palmas De Gran Canaria, Spain

Disclosure: Nothing to disclose.

Raphael J Kiel, MD, Associate Professor of Medicine, Wayne State University School of Medicine; Associate Professor of Medicine, Oakland University William Beaumont School of Medicine; Consulting Staff, Infectious Diseases Division, William Beaumont Hospital; Consulting Staff, Infectious Diseases Division Providence Hospital

Disclosure: Nothing to disclose.

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Mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.

Frontal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.

MRI coronal section of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. On this T1-potentiated image, a large heterogenous mass surrounds the cranium. Bone invasion can be observed only in the area of the zygomatic fossa.

MRI with coronal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. The mycetoma mass invades the left parapharyngeal space and almost reaches the lumen of the pharynx.

Mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.

Frontal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years.

MRI coronal section of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. On this T1-potentiated image, a large heterogenous mass surrounds the cranium. Bone invasion can be observed only in the area of the zygomatic fossa.

MRI with coronal view of mycetoma in a 47-year-old shepherd from Mauritania who had a painless progressive swelling of the face for more than 20 years. The mycetoma mass invades the left parapharyngeal space and almost reaches the lumen of the pharynx.