Mycetoma 

Updated: Apr 07, 2021
Author: Lucio Vera-Cabrera, PhD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 

Overview

Practice Essentials

Mycetoma is a chronic, granulomatous disease of the skin and subcutaneous tissue, which sometimes involves muscle, bone, and neighboring organs.[1] 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 appear in the general population.[2, 3, 4]

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.[5] The disease presentation, whether caused by fungi or bacteria, is quite similar.

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.[6] 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 cervicofacial, 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 56 different species of fungi and bacteria have been reported to cause mycetoma. Nocardia species, especially Nocardia brasiliensis, is the most commonly implicated actinomycetes.[7] The ratio of mycetoma cases caused by bacteria (actinomycetoma) to those caused by true fungi (eumycetoma) in Mexico has been reported to be 92:8.[8]

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

Actinomycetoma generally responds well to trimethoprim-sulfamethoxazole/amikacin (approximately 90% of cases). If the bacteria have become resistant to this treatment, antibiotic susceptibility testing should be performed to select the best antimicrobial agent or agents to be used. Linezolid and tedizolid, of the group of the oxazolidinones, have been proved useful in vitro, in vivo, and in some human clinical cases,[9] although the expensive price hinders their use in poor developing countries, where most cases are reported.

Eumycetoma tends to be a more chronic disease, and success with medical therapy is observed in only about 40% of cases. If the response to medical treatment is partial or negative, surgery of the affected area should be performed, and antifungal drugs should be continued until complete remission of the disease.

Background

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 1913, 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.[10]

Pathophysiology

Mycetoma is produced by the introduction of microorganisms (bacteria or fungi) via localized trauma to 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 lesions that in some cases can reach more than 20 cm in diameter. Eumycetoma tends to be more localized than actinomycetoma.

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.[11]

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.

In experimentally induced N brasiliensis actinomycetoma in mice, production of granules (or grains) containing the bacterium can be observed 15 days after inoculation. The grains are surrounded by polymorphonuclear leukocytes, 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 in situ production of cytokines in the microabscesses has been reported in murine infection. Tumor necrosis factor-alpha is produced in the first days of infection, decreasing later to nondetectable quantities at day 90. Interleukin (IL)–1-beta, interferon-gamma, transforming growth factor-beta, IL-10, IL-4, and IL-6 are produced constantly during the 90 days, but IL-6 is the only one with a significant increase once the mycetoma is fully established (90 d).[12]

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 useful for diagnosis.[13] Immunoglobulin M anti–N brasiliensis antibodies can protect mice from an experimental infection.[14] Activation of cellular immunity and production of cytokines are involved in resistance and elimination of the N brasiliensis bacterial cells.

Salinas-Carmona et al (2012) have unveiled aspects of the physiopathogenic mechanisms of experimental actinomycetoma in mice.[15]

Etiology

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.

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

Eumycetoma is mainly caused by Madurella mycetomatis, which produces 70% of all eumycetoma cases globally. Less frequently, Trematosphaeria (Madurella) grisea, Scedosporium boydii, and Falciformispora (Leptosphaeria) senegalensis are isolated.[16] Other Madurella species have been identified in cattle dung in rural East Africa.[17]

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

Although traditionally it has been considered that mycetoma is produced by the pathogenic characteristics of the causative agents, it has been observed that genetic polymorphisms involved in neutrophil function are related to either the production of human mycetoma or its size, in the case of M mycetomatis infection. IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4, nitric oxide synthase, and complement receptor 1 have significant differences in mycetoma patients compared with geographically and ethnically matched controls. These findings open the possibility that certain individuals are predisposed to this infection.[18]

The use of molecular methods has permitted the identification of new species causing mycetoma, including Nocardia harenae, Nocardia wallacei, and Nocardia takedensis, and Actinomadura mexicana causing actinomycetoma.[19, 20, 21] Madurella fahalii, Aspergillus sydowi, and Microascus gracilis are identified as causing eumycetoma.[22, 23]

Table 1. Fungi Causing Mycetoma (Open Table in a new window)

White Grain

Black Grain

Acremonium falciforme

Exophiala jeanselmei

Acremonium kiliense

T grisea

Acremonium recifei

M mycetomatis

Cylindrocarpon destructans

Madurella pseudomycetomatis

Fusarium moniliforme

Leptosphaeria tomkinsii

Fusarium solani

Leptosphaeria senegalensis

Neotestudina rosatii

Pyrenochaeta mackinnonii

P boydii (S apiospermum)

Pyrenochaeta romeroi

----------------

Phlenodomus avramii

Table 2. Microorganisms Causing Actinomycetoma in Humans (Open Table in a new window)

Etiologic Agent

Grain

Actinomadura madurae

White, large, 1-5 mm in diameter

Actinomadura pelletieri

Red, hard, 1 mm in diameter

N brasiliensis

White to yellow, multilobed, soft, < 0.5 mm in diameter

N asteroides

Uncommon, white, soft, < 0.5 mm in diameter

Nocardia otitidiscaviarum

White to yellow, lobed, < 0.5 mm in diameter

Nocardia transvalensis

White to yellow, < 0.5 mm in diameter

Nocardia veterana[24]

--

Nocardia mexicana[25]

--

N harenae

--

N takedensis

--

Nocardiopsis dassonvillei

White to yellow, < 0.5 mm in diameter

S somaliensis

Yellow, hard, 2 mm in diameter

Streptomyces sudanensis

Yellow, hard, 2 mm in diameter

Epidemiology

Mycetoma is endemic in Africa, in the known “mycetoma belt” that comprises countries like 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.[26]

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)[27] and has been described in Southeast Asia.[28]

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.[29]

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, M mycetomatis is the most common pathogen described in Africa.[30] T grisea is the most common etiologic pathogen in South America. P boydii (S apiospermum) is the most common etiologic agent in the United States.[30] In Mexico, which shares common climatic conditions with the African countries, most cases are found in rural areas and 98% are caused by actinomycetes, mainly N brasiliensis (86%) and A madurae (about 8%).[31] In India, 65% of cases are produced by actinomycetes and the rest by eumycetes, mostly M mycetomatis.[30]

Mycetoma has no apparent racial predilection. Mycetoma is more common in men than in women, with male-to-female ratios ranging from 3:1 to 5:1. It is most common in persons aged 20-50 years, with a mean of age 34 years.

Prognosis

Mycetoma carries a good prognosis if the disease is promptly diagnosed and treated. Mycetoma causes disfigurement but is rarely fatal in the absence of skull involvement. Although mycetoma carries a low risk of mortality, amputations or ankylosis can lessen the quality of life.[32] In late stages of mycetoma, the treatment response is limited.

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.[33] 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.

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. Secondary bacterial infections can progress to full-blown bacteremia or septicemia, resulting in death.[6]

See the images below.

Mycetoma in a 47-year-old shepherd from Mauritania 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 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.
 

Presentation

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.

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 Examination

Irrespective of the causal agent, the appearance of the mycetoma lesion is consistent. Initially, subcutaneous swelling is present. In a later phase, a subcutaneous nodule develops. Eventually, massive swelling with induration, rupture of the skin, and formation of sinus tracts occur.

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.

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

The most common anatomical locations affected by this disease are the arms and legs, particularly the feet and 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, groin, head, and neck.

 See the images below.

Actinomycetoma of the foot (left) and arm (center) Actinomycetoma of the foot (left) and arm (center) caused by Nocardia brasiliensis. Multiple nodules and fistulae are present. Microscopic examination of the pus (right). Granules are observed, which are multilobulated and surrounded by abundant clubs.
Eumycetoma. Mycetoma of the hand (left). Microscop 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, Scedosporium apiospermum (Pseudallescheria boydii) (right).

Regional lymphadenopathy is unusual. Lymphatic spread of mycetoma to regional nodes occurs in only 1-3% of affected patients. Secondary bacterial infection or a local immunologic reaction may enlarge the regional lymph nodes. 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.

 

DDx

 

Workup

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.[34]

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.[35] Differentiation is accomplished by microscopic examination of exudate from the draining sinuses. Actinomycetes have granules of about 100 µm in diameter, with delicate, branched filaments measuring about 1 µm in diameter. In contrast, 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 pus from the abscess or the fistula and by tissue biopsy of the affected site. 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.

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 three 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 enzyme-linked immunosorbent assay (ELISA) to detect antibodies against N brasiliensis.[36, 37] A correlation between antibody titers and clinical condition of the patients was observed. In individuals with active disease, titers were high. In patients with cured lesions, titers were below the cut-off point, with results similar to those obtained with negative controls. To date, the use of a skin antigen for diagnosis has not been useful because of cross-reactivity with other bacterial infections, such as tuberculosis or leprosy.

Regarding eumycotic mycetoma infections, immunodiffusion tests have been used to detect antibodies. In the case of mycetoma caused by M mycetomatis, an immunodominant protein that induces specific antibodies has been described; these antibodies are useful for the identification and prognosis of this infection. A good animal model for studying eumycotic mycetoma has not yet been developed.

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.[36, 38]

An ELISA to determine anti–N brasiliensis antibodies is used for diagnosis and to assess response to medical treatment.[13] Immunoblotting for M mycetomatis identification has been reported.[39]

Advances in genomics have achieved the specific sequence of some pathogenic actinomycetes, among them N brasiliensis, identified by Vera-Cabrera et al.[40] New therapeutic agents in experimental infections in mice, which could be useful in human disease, have also been identified.[41, 42, 43]

Laboratory 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:

  • Actinomycetoma - Homogenously eosinophilic with hematoxylin-eosin stain; blue in the center with pink filaments in the periphery with May-Grünwald-Giemsa stain
  • Eumycetoma - Brownish color with hematoxylin-eosin stain; black with a green tinge with May-Grünwald-Giemsa stain

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

  • Tissue Gram stain to detect fine, gram-positive, branching filaments within the actinomycetoma grain
  • Gomori methenamine silver or periodic acid-Schiff stain to demonstrate the larger hyphae of eumycetoma

Evaluation of the characteristics of the associated granules suggests an initial differential diagnosis. White-to-yellow grains indicate P boydii (S apiospermum), Nocardia species, or A madurae infection. Yellow-to-brown grains indicate S somaliensis infection. Black grains indicate Streptomyces paraguayensis, Madurella species, or Leptosphaeria species infection. Red-to-pink grains indicate A pelletieri infection.

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) ELISA, or (4) Western blot.

Imaging Studies

Bone radiography

Only 3% of patients with mycetoma have normal radiographs.[44]

Once mycetoma has invaded the bone, changes may be observed. Cortical thinning is due to compression from the outside by the mycetoma. Cortical hypertrophy or periosteal proliferation may present as a sunray appearance and a Codman triangle. Multiple lytic lesions or cavities may be large and few in number with well-defined margins (eumycetoma) or small and numerous with ill-defined margins (actinomycetoma). Disuse osteoporosis may occur in late stages mycetoma.

Magnetic resonance imaging

MRI helps with the differential diagnosis and the assessment of the degree of bone and soft-tissue involvement.[45] The dot-in-circle sign is an easy-to-recognize and highly specific MRI sign of mycetoma.[46, 47]

See the images below.

MRI coronal section of mycetoma in a 47-year-old s 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 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.

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 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.[48] Fine-needle aspiration cytology allows differentiating actinomycetoma from eumycetoma.[49]

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.[50]

Staging

Bone involvement has been radiographically classified, as follows:

  • Stage 0 - Soft-tissue swelling without bone involvement
  • Stage I - Extrinsic pressure effects on the intact bones in the vicinity of an expanding granuloma
  • Stage II - Irritation of the bone surface without intraosseous invasion
  • Stage III - Cortical erosion and central cavitation
  • Stage IV - Longitudinal spreading along a single ray
  • Stage V - Horizontal spread along a single row
  • Stage VI - Multidirectional spread due to uncontrolled infection
 

Treatment

Approach Considerations

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

In the treatment of mycetoma, antibiotic or antifungal therapy should be attempted first and may need to be combined with surgery,[6] especially for eumycetoma lesions in the extremities.[51]

External beam radiotherapy in doses ranging from 3.5-14 Gy has been considered successful treatment in a few selected cases.[52]

Medical Care

Eumycetoma

Although eumycetoma may respond partially to antifungal agents, surgical removal is usually done first.[53] 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 adverse effects and multiple drug interactions.[54] Fluconazole is also discouraged because of intrinsic resistance.[55]

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 M mycetomatis, but terbinafine is only moderately active. Since posaconazole has an excellent safety profile, it might provide an important alternative in mycetoma therapy.[56]

M mycetomatis is not susceptible to the echinocandins.[57]

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.[58, 59] Therapy is suggested for 1-2 years (or greater) for complete eradication, unless adverse effects warrant cessation of medication.

In two cases, the combination of itraconazole and terbinafine has been used, resulting in remission of the disease.[60] Combined medical and surgical treatment is a viable therapy for mycetoma caused by fungi.

Actinomycetoma

Actinomycetoma is a bacterial infection that can respond to antibiotics[61] if treatment is administered early in the course of the disease.[62] A combination of two 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, dapsone (diaminodiphenylsulfone), and streptomycin sulfate. Amikacin can be substituted for streptomycin but is usually kept as a second-line drug because of its cost.

Current treatment of actinomycetoma is trimethoprim-sulfamethoxazole 7.5-40 mg/kg daily divided in two 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 or intravenously daily should be added.[63] Every 3 weeks, periodic audiometric and creatine clearance analysis must be performed. This treatment is maintained for 5-20 weeks and, in rare cases, for a longer period, depending on the clinical response and renal and auditory adverse effects.

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.[64] However, a case of actinomycetoma was reported as still improving after 5 years of continued treatment with cotrimoxazole only.[65]

In one case report, a patient required salvage therapy with amikacin and imipenem for 6 months.[66] 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.[67, 68]

Other antimicrobials such as minocycline, amoxicillin-clavulanic acid, streptomycin, imipenem, meropenem, and rifampin have been used with variable success.[61, 69] 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 (tedizolid) are active in vitro and in experimental models of N brasiliensis infection, and its successful use in human nocardiosis opens the possibility to treat actinomycetoma cases caused by Nocardia species.[9, 70]

Fluoroquinolones such as gatifloxacin and moxifloxacin have been observed to be active in vitro and in a murine model of actinomycetoma by N brasiliensis. However, clinical assays are necessary to determine their usefulness in human cases.[71, 72]

Regarding treatment, refer to the article "Actinomycetoma and advances in its treatment" by Welsh et al, which outlines current treatment for unresponsive or disseminated infection.[61, 73, 74]

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.[75] However, partial surgical resection without subsequent use of appropriate antimicrobial or antifungal agents is prone to failure.

In eumycetoma, surgical therapy is an option if the patient's disease has not responded to antifungal medical treatment, in local lesions, and in patients with massive disease. In these cases, wide local and debulking excisions and even amputation are used together with medical fungal treatment.[76, 77]

In actinomycetoma surgical treatment, including amputation, is infrequently indicated.

Consultations

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

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.[17] 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.[78]

Long-Term Monitoring

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

 

Medication

Medication Summary

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 an 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.

Antibiotics

Class Summary

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

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

Doxycycline is a drug of choice. It is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. It inhibits protein synthesis and, thus, bacterial growth by binding to the 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Trimethoprim-sulfamethoxazole (Bactrim DS, Septra)

Trimethoprim-sulfamethoxazole is a drug of choice; it inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. It should be used continuously in combination with another antimicrobial for a 5-week cycle. The cycle may be repeated as necessary.

Amikacin (Amikin)

Amikacin irreversibly binds to the 30S subunit of bacterial ribosomes, blocks the recognition step in protein synthesis, and causes growth inhibition. It should be given continuously for 3 weeks. Although somewhat expensive, it usually is active against the bacteria causing actinomycetoma. Use the patient's ideal body weight for dosage calculation.

Dapsone (Avlosulfon)

Dapsone is bactericidal and bacteriostatic against mycobacteria. Its mechanism of action is similar to sulfonamides, where competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth. It is the lowest-cost regimen. Change to trimethoprim-sulfamethoxazole if no response occurs after 1 month.

Rifampin (Rimactane, Rifadin)

Rifampin is for use in combination with at least one other agent. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur.

Imipenem and cilastatin (Primaxin)

This combination is for treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to the potential for toxicity.

Gentamicin (Garamycin)

Gentamicin is an aminoglycoside antibiotic for coverage of gram-negative bacteria, including Pseudomonas species. It is synergistic with beta-lactamase against enterococci. It interferes with bacterial protein synthesis by binding to the 30S and 50S ribosomal subunits. Dosing regimens are numerous and are adjusted based on creatinine clearance and changes in the volume of distribution, as well as the body space into which the agent needs to distribute. Gentamicin may be given IV/IM. Each regimen must be followed by at least a trough level drawn on the third or fourth dose, 0.5 hour before dosing; one may draw a peak level 0.5 hour after a 30-min infusion.

Antifungal agents

Class Summary

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

Ketoconazole (Nizoral)

Ketoconazole has fungistatic activity. It is an imidazole broad-spectrum antifungal agent; it inhibits the synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

Itraconazole (Sporanox)

Itraconazole has fungistatic activity. It is a 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)

Amphotericin B is a polyene antibiotic produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. It binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.

The 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)

Voriconazole is used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or S apiospermum infections. It is a triazole antifungal agent that inhibits fungal cytochrome P-450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.