Dermatology

Mycetoma (Madhura foot, Madhura mycoses; Eumycetoma: Eumycotic mycetoma, Maduromycotic mycetoma; Actinomycetoma: Actinomycotic mycetoma, Actinomycetic mycetoma)

Are You Confident of the Diagnosis?

Mycetoma is a localized chronic subcutaneous infection caused by true fungi or Actinomycetales (fungus-like bacteria) clinically characterized by the triad of tumefaction, sinuses and discharge containing typical grains. Mycetoma caused by fungi is called eumycetoma and that caused by bacteria is called actinomycetoma.

  • What you should be alert for in the history

Progression of the lesion from initial traumatic inoculation to subsequent development of classic lesion of mycetoma is elicited in the history. The disease usually manifests several months after the inoculation of the causative agent. The initial lesion is a small, firm, painless subcutaneous nodule that increases gradually in size. Subsequent evolution and progression or behavior of the infection differs in eumycetoma and actinomycetoma. The rate of disease progression is relatively rapid with extensive destruction of tissue in actinomycetoma when compared with eumycetoma.

Gradually new nodules appear and may coalesce to form larger, multilobular nodules or tumor-like mass. Over the next few months, the nodules soften at the surface and ulcerate, discharging purulent fluid containing characteristic grains (Figure 1). Sometimes these ulcers and sinuses show exuberant granulation tissue and crusting (Figure 2). During ensuing months the lesion broadens out and also spreads to deeper tissues like muscles and bones. As new lesions appear, the older lesions heal, resulting in depigmented and scarred skin.

Figure 1.

Diffuse swelling with multiple nodules discharging purulent material affecting dorsum of right foot.

Figure 2.

Actinomycetoma on the left arm, shoulder and adjacent neck region showing extensive crusting and exuberant granulation tissue.

The cycle of swelling, suppuration and scarring recurs at the site of infection, ultimately leading to classic triad of mycetoma. The end result is a swollen, deformed mass of destroyed tissue with several sinuses discharging grains. The time required for these steps to occur is not clearly defined. However, sinuses take at least 3 months to appear. In one third of patients, sinuses form in 3 to 6 months, and by the end of 1 year almost all patients develop sinuses.

  • Characteristic findings on physical examination

Regardless of the type of mycetoma, the clinical manifestations are similar except for a few differences (Table I).

Table I.

Differences between eumycetoma and actinomycetoma
Characteristics Eumycetoma Actinomycetoma
Etiology Filamentous fungi Fungus-like bacteria
Progression of disease Slow Rapid
Site of involvement Feet and hands Involvement of covered parts almost always suggests actinomycetoma
Swelling Well circumscribed, and marked in the later stage Less well defined and merges with surrounding tissue
Tissue destruction Marked in the later stage Involvement of bone is earlier and extensive
Radiology of bones Larger and less numerous cavities with well defined walls and little sign of bone destruction Smaller and abundant cavities with extensive fuzzy destruction bone (A pellitieri, S somaliensis), Large multiple cavities with limited destruction (A madurae), extensive bone destruction with no cavities (N asteroides)
Grains Dark with a coarser texture easily visible to naked eye Small, pale with a fine texture difficult to see with naked eye
Filaments Wide (2-5mm) and septate hyphae, Periodic Schiff (PAS) positive and gram-negative easily visualized at ×400 Slender (0.5-1mm) and nonseptate, PAS negative and gram-positive filaments difficult to visualize even at ×800
Response to medications Unresponsive and requires surgical debulking Good response

The affected patients present at a later stage of the disease with tumefaction, nodular swellings, sinuses and discharge containing characteristic grains. Most mycetoma cases are painless. The presence of constitutional symptoms indicates secondary bacterial infection.

The predominant site of involvement is the foot, accounting for two thirds or more of cases. Other sites of involvement are the hands, knees, scalp, neck, chest, abdomen, arm, buttocks, perineum, and shoulders. The involvement of covered parts of the body is almost always suggestive of actinomycetoma. This difference is mainly due to the ability of the organisms to colonize short-term shallow wounds, local bacterial flora and temperature of the anatomic region. These factors, to some extent, vary between exposed and covered parts, resulting in different etiologic agents. In the majority of patients presenting with head and neck disease, actinomycetoma cases constitute the most predominant type of mycetoma.

Grains are aggregation of causative agents. The color, size, and texture of grains help in identification of causative organisms (Table I). Nocardiae do not clump together readily. Hence grains are rarely identified in purulent discharge.

  • Expected results of diagnostic studies

The identification of the causative organism is crucial for optimum management of patients with mycetoma. Currently, multiple diagnostic tools are used such as various imaging, cytological, histopathological, serological, and culture techniques; phenotypic characterization; and molecular diagnostics to determine the extent of infections and to identify the causative agents of mycetoma. However, there is no ideal diagnostic tool available. Future research should focus on the development of new and reliable diagnostic tools.

The grains are obtained by puncturing a softened nodule using a sterile syringe with a #18 gauge wide-bore needle. Grains can also be obtained by aspiration of secretions flowing from the sinus. Cotton swabs are avoided, as the fibers may interfere with microscopic identification of hyphae or filaments. Small fragments of tissue should be removed if there is no pus. A deep wedge biopsy provides a good specimen for culture, as it is free of bacterial and fungal contaminants. At least 20 to 30 grains should be obtained

The grains should be rinsed quickly in 70% alcohol and washed several times in sterile saline before inoculating into culture media. For direct microscopy, the grains are crushed between two slides. The processed specimen is subjected to potassium hydroxide preparation, Gram staining, and modified Ziehl-Neelson staining with 1% sulphuric acid. Under light microscope, the fungal elements appear as broad septate hyphae and bacteria appear as slender nonseptate filaments (see Table II). Nocardia spp are weakly acid-fast.

Table II.

Etiology of mycetoma
Mycetoma Genus Species Color of grains
Eumycetoma Madurella mycetomatis Hard, Black
grisea Soft, Black
Pyrenochaeta romeroi Soft, B
Leptosphaeria senegalensis Soft, Black
Exophiala jeanselmei Soft, Black
Curvularia lunata Soft, Black
Pseudoallescheria boydii Soft, Large white to yellow
Neotestudina rosatii Soft, Large white to yellow
Acremonium spp -- Soft, Large white to yellow
Fusarium spp -- Soft, Large white to yellow
Actinomycetoma Actinomadura madurae Soft, White to yellow /cream
pelletieri Soft, Red to pink
Nocardia brasiliensis Soft, Small white to yellow
asteroides Soft, Small white to yellow
caviae Soft, Small white to yellow
Streptomyces somaliensis Soft, Yellow/brown

The definitive diagnosis of mycetoma is established by isolation of the causative organism; however, culture positivity has been reported in only 50% of actinomycetoma cases.

Various factors have been suggested to explain the low percentage of culture positivity such as stringent growth requirements, frequent contamination of specimens, small numbers of viable organisms present in longstanding and very inflammatory lesions, paucity of grains within the tissue from either prior partial treatment or robust immune response to infection, sampling error, inadequate material from a punch biopsy and a late presentation of the patient when fibrosis predominates over purulent discharge.

Sabourads dextrose agar (SDA) without antibiotics but with cycloheximide is commonly used for isolation of organisms causing actinomycetoma. For eumycetoma, SDA with antibiotics but without cycloheximide is used.

Isolation of Nocardia spp using ordinary culture media is a difficult process. Because of slow growth rate, the small colonies of Nocardia spp are usually overgrown by other rapidly growing organisms resulting in negative culture report. Hence, a selective media is necessary to enhance the recovery of Nocardia spp. To overcome the growth of contaminating organisms, a chemically defined media containing paraffin agar has been suggested for selective isolation of Nocardia spp.

Nocardia spp grow readily on carbon-free agar containing paraffin, paraffin-gelatin and paraffin-urea when compared with growth on blood agar. Similarly, growth of Streptomyces spp is enhanced on agar containing gelatin, urea, paraffin-gelatin and paraffin-urea when compared with paraffin and blood agar.

Unlike Nocardia spp, the Actinomadura madurae and Streptomyces spp do not grow on nutrient broth with lysozyme. The organisms causing actinomycetoma usually take 10 days to 2 weeks for growth. In case of no growth, the culture media should be incubated for at least 6 weeks before labeling it as negative growth.

For fungal culture, the specimen is initially inoculated in blood agar and later for subcultures in Sabouraud 2% dextrose agar.

HISTOPATHOLOGY

In culture-negative patients, demonstration of grains and associated histopathologic features help in administration of appropriate therapy. Sometimes serial sections are required to demonstrate grains. Both types of mycetoma show similar histopathologic changes. However, cellular reaction would be more severe in actinomycetoma.

The characteristic histopathologic feature is grains surrounded by suppurative inflammatory response consisting predominantly of neutrophils. There may be associated granulomatous reaction with varying proportion of epithelioid cells, plasma cells, lymphocytes and giant cells. Homogenous eosinophilic material surrounding the grain, commonly known as Splendore - Hoeppli phenomenon, is diagnostic of mycetoma (Figure 3). Other features include fibrosis and endarteritic changes.

Figure 3.

Mixed inflammatory infiltrate composed of neutrophils, eosinophils, plasma cells and macrophages in the dermis with blue grains surrounded by homogenous eosinophilic material, Splendore-Hoeppli phenomenon (arrow). (H&E x200)

Tissue section stained with Gram stain identifies filamentous bacteria in actinomycetoma, whereas Gomori methenamine silver or PAS staining detects fungal hyphae.

Three types of tissue reaction have been observed around the grain in Madurella mycetomatis:

Type I: Neutrophils adhering to the surface of grain and destroying the structure

Type II: Fragments of grain, dead neutrophils removed by macrophages

Type III: Epithelioid granuloma with Langerhans’ giant cells

Fine-needle aspiration cytology (FNAC) is an effective method for rapid diagnosis of mycetoma, but it is valuable only in the case of aspiration of granules.

IMAGING STUDIES

The extent of spread of the disease and involvement of bone and adjacent viscera can be assessed by imaging studies. However, causative organisms cannot be identified.

X-ray

Radiologic changes in bones are late sequelae of the disease. The basic radiologic changes of osseous structures include osteoporosis, loss of cortical margin, erosion, lytic lesions and bony expansion. The tarsometatarsal region is commonly affected in mycetoma. Characteristics of radiologic changes (see above) help to identify causative organisms (see Table II).

Ultrasonography (USG)

Typical USG findings differentiate between eumycetoma and actinomycetoma. USG is safe, accurate and useful in planning surgical treatment. It is better than clinical examination in assessing the extent of disease involvement. Ultrasound-guided aspiration biopsy showed 100% efficacy in reaching the abscess, and identification of grains in 60% of cases.

Magnetic resonance imaging (MRI) and computed tomography (CT)

A "dot in the ring" sign in MRI (T2-weighted, Short Tau Inversion Recovery (STIR), and T1-weighted fat-saturated gadolinium-enhanced images) has been reported as the early sign of mycetoma. It is characterized by small central hypointense foci representing the grains, and the surrounding high-signal intensity foci represent inflammatory granuloma. Nodular, MRI-detected structures, named "M nodules" are considered to be pathognomonic of mycetoma. MRI readily detects late manifestations of mycetoma such as coarse trabecular pattern, bone destruction, marrow infiltration and sequestra.

CT scan shows greater sensitivity in the detection of early bone changes such as periosteal elevation, cortical hyperostosis, cortical erosions and osteal proliferations.

MRI and CT are considered as accurate diagnostic tools to determine the disease extent involving the head and neck region.

SEROLOGY

Serodiagnosis is considered when repeated culture results are negative. Newer molecular modalities, such as polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA) and immunoassays, are now available in limited centers for serodiagnosis.

ELISA has been utilized successfully for specific diagnosis and evaluation of therapeutic response in actinomycetoma caused by N brasiliensis. PCR via amplification of 16s rDNA, a species-specific gene sequence, has been developed in the diagnosis of Nocardia spp. PCR has also been used to identify new species and phylogenetic relationships.

Several organisms have been implicated in the etiology of mycetoma. Therefore, serodiagnosis for species is considered based on the prevalence of causative organisms, clinical clues and availability of serologic tests.

  • Diagnosis confirmation

DIFFERENTIAL DIAGNOSIS

The patient presenting with a painless, firm, subcutaneous nodule with or without sinuses should be considered as having mycetoma until otherwise proved.

In early stages, chronic bacterial osteomyelitis secondary to tuberculous, actinomycotic or syphilitic infections resembles mycetoma. Mycetoma without sinuses should be differentiated from soft tissue tumors such as a lipoma or cystic lesions like a cold abscess or implantation dermoid. Chromoblastomycosis, cutaneous tuberculosis, syphilitic gumma, leprous nodules and other nodular conditions also need to be differentiated.

All the above conditions can be differentiated by characteristic sinuses discharging grains; however, botryomycosis and pseudomycetoma caused by dermatophytes also produce grains. The former is caused by a number of gram-positive cocci and gram-negative bacilli, and the disease also involves viscera. The latter is caused by some dermatophytes and never involves bones.

Who is at Risk for Developing this Disease?

Epidemiology

Generally, mycetoma is worldwide in distribution; however, the disease is more prevalent in arid, tropical, and subtropical countries. A recent epidemiological study from Sudan spanning two decades and involving 6,792 patients revealed the following findings:

  • The patients were predominantly young (64% <30 years old) males (74%).

  • In 66% of the patients, the duration of the disease was less than 5 years, and 81% gave a history of sinuses discharging mostly black grains (78%).

  • History of trauma was present in 20%.

  • M. mycetomatis eumycetoma was the most common type (70%).

  • History of previous treatment was present in 4%.

  • The foot (76%) and hand (8%) were the most commonly affected sites. Less frequently affected sites were the leg and knee (7%), thigh (2%), buttock (2%), and arm and forearm (1%).

  • Rare sites included the chest wall, head and neck, back, abdominal wall, perineum, oral cavity, tongue and eye.

Geographic distribution

The geographic distribution of causative organisms of mycetoma is influenced by the climate. The geographic area between latitude 15°S and 30°N is considered as the mycetoma endemic belt. The endemic areas are delineated by altitude, temperature, rainfall, type of soil and vegetation. The endemic areas have a short rainy season (200 to 500mm of rainfall) of 4 to 6 months with relative humidity of 60% to 80% and temperature of 30° to 37°C. The dry season is of 6 to 8 months' duration with relative humidity of 12% to 30% and a temperature of 45° to 60°C.

The countries that fall in this geographic area include Sudan, India, Brazil, Mexico, Venezuela, Senegal, Somalia, Zaire, Pakistan and Middle Eastern countries. Eumycetoma is predominant in the regions (countries surrounding the Saharan and Arabian deserts) with high temperature, dry environment and low-to-medium rainfall. Actinomycetoma is predominant in relatively humid regions (India and Latin America) with cooler temperature and high rainfall.

Pseudoallescheria boydii is commonly isolated from temperate regions like the United States of America.

Race and ethnicity: Race and ethnic distribution of the disease reflects the people living in the endemic area.

Gender distribution

Males are four to five times more predisposed to the infection than females. The risk of males to develop mycetoma on an exposed site is three times higher than that of females; however, the gender distribution is equal for mycetoma on covered parts.

The gender difference is not necessarily due to occupational risk; it has been attributed to inhibition of M mycetomatis growth by progesterone.

Age distribution

All age groups are susceptible to contract infection following traumatic inoculation of the causative organisms. The individuals in fourth and fifth decades are more susceptible to develop mycetoma. The disease is rare in children owing to the long incubation period and gradual progression of the infection. The head and neck disease was found to be more common in young male patients.

Populations at risk

  • Agricultural workers

  • Barefoot outdoor workers

  • People residing in rural areas

  • Malnutrition, poverty

  • Individuals with single nucleotide polymorphism (SNP) in the chitotriosidase gene, resulting in decreased activity of the enzyme, are at increased risk of developing mycetoma caused by M. mycetomatis.

  • The functional SNPs in chemokine ligand 5 (CCL5) and IL-10 result in increased serum levels of CCL5 and IL-10. These SNPs in patients with mycetoma are associated with a granuloma formation.

Mode of transmission

The organisms always gain entry through traumatic inoculation. Trauma is often due to vegetable matters (thorn, grasses, wisp of straw and hay). Prick injuries from thorn, wood spicule, plant fiber, nail or needle are predominant modes of inoculation of organisms; however, operative wounds, wide open injuries, and shallow surface injuries (scratches, friction) can also predispose to the entry of organisms.

What is the Cause of the Disease?

  • Etiology

Several species of true fungi and aerobic Actinomycetales belonging to genera Actinomadura, Nocardia and Streptomyces are the common etiologic agents of mycetoma (Table II). The majority of these organisms are saprophytes of soil or vegetative matter.

Other rare fungi implicated in the etiology of eumycetoma are Aspergillus flavus, Aspergillus nidulaus and Neoscytalidium dimidiatum.

  • Pathophysiology

Once gaining entry into the subcutaneous tissue, the causative agents have to evade host defense and elicit an immune response to manifest the disease.

Immune response: Abnormal cell-mediated immune responses have been reported in severely infected patients and in those who did not respond to therapy. However, other studies revealed no such abnormalities.

Evasion of host defense: Structural alterations that occur in fungal cell wall help to evade the host defense. The cell walls of fungal elements, especially at the periphery of the grain, become thickened, showing alternating electron-dense and electron-lucent zones, and fuse with each other. Polysaccharide cytoskeletons of fungal cell wall are also produced in excess. These structural changes in the cell wall make the fungus less penetrable to antifungal drugs, respiratory burst products, and polysaccharide adhesion molecules that may interfere with cell wall-leukocyte interaction.

M. mycetomatis and M. grisea elaborate an extracellular cement, 1,8-dihydroxynaphthalene (DHN) melanin, which binds to tissue debris and proteins, thereby strengthening the fungus against antibodies, hydrolytic enzymes and antifungal agents.

Systemic Implications and Complications

  • Local complications

Secondary bacterial infections

The presence of constitutional symptoms usually indicates a secondary bacterial infection. The discharge becomes more copious and purulent with foul odor. Regional lymphadenopathy is common.

Local spread of the disease

The local spread of infection occurs along the fascial planes involving muscles, ligaments and bones. The tendons and nerves are resistant to invasion. Involvement of bone is responsible for severe morbidity associated with mycetoma. The causative agents invade the medullary canal and epiphysis leading to destruction of bone. Osteomyelitis can result in complete destruction of bone. The foot becomes shortened due to destruction of tarsal bones and extensive plantar fibrosis. Chronic periarticular fibrosis manifests as joint stiffness, and chronic pressure and inactivity due to swelling result in osteoporosis.

  • Systemic complications

The infection never spreads hematogenously. Lymphatic spread occasionally results in regional lymphadenopathy. Internal viscera may be affected due to lymphatic spread from the initial subcutaneous disease.

Lung involvement with pleural effusion can occur secondary to contiguous spread of the disease from mycetoma involving chest wall. Similarly, mycetoma of leg, thighs and perineum may cause abdominal and visceral involvement. Spinal cord compressions and paraplegia can occur secondary to involvement of vertebral bodies. Primary involvement of viscera by mycetoma has not been demonstrated.

Treatment Options

In treating patients with a mycetoma, the successful therapeutic outcome depends on the definitive identification of the causative organism. The knowledge of prevalent organisms causing mycetoma and their susceptibility pattern in a geographic area is essential for administration of empirical treatment as the isolation of causative organisms is not always successful.

Affordability of medications and compliance of the patient are also very important. Patients with mycetoma usually present late with advanced disease, which is attributed to lack of medical and health facilities in endemic areas, poor health education, and low socio-economic status. To overcome these obstacles, a new model of management of mycetoma has been successfully developed in Sudan. It includes surgical treatment in a mobile surgery unit and health education to improve the knowledge, attitude, and practice among the individuals regarding mycetoma. Actinomycetoma generally responds well to antimicrobial therapy. Eumycetoma requires surgical debulking along with antifungal therapy.

A rapid response following the addition of oral diclofenac (100mg/day) to antifungal therapy has been reported recently in patients with mycetoma of 20 years duration. It indicates the role of inflammation in disease activity and the potential role of antiinflammatory drugs in the management of mycetoma. However, further well designed studies are required to demonstrate their efficacy.

Mycetoma of the head and neck region, though rare, is associated with high morbidity and even high mortality if not treated early. In these patients, the response to treatment is poor, characterized by low cure rates, poor outcome, and high follow-up dropouts.

The clinical predictors of cure and dropouts among patients with mycetoma have been determined. In eumycetoma, a longer duration of therapy and absence of disease recurrence are significant predictors of increased odds of cure, whereas a lesion size of 5-10 cm or >10 cm and combined medical treatment and surgery are significant predictors of reduced odds of cure. Larger lesions, longer duration, and amputation are predictors of reduced odds of dropouts. In actinomycetoma, medical treatment is the only significant predictor of cure and longer treatment duration is the predictor of reduced odds of dropouts.

Optimal Therapeutic Approach for this Disease

Consultation with an Infectious disease specialist is recommended.

  • Actinomycetoma

Early diagnosis and administration of appropriate therapy is essential for better therapeutic outcome. Proper patient counseling is important as the disease requires prolonged therapy for several months.

A combination therapy with two or three drugs (Table III) is advised by many to prevent the acquisition of resistance; increase the efficacy of drugs and shorten duration of treatment. Treatment with cotrimoxazole, gentamicin/amikacin and doxycycline is effective against all the organisms causing actinomycetoma. In case of visceral involvement, especially lung and vertebra, use combination therapy with parenteral amikacin and oral cotrimoxazole.

Table III.

Drugs used in the treatment of actinomycetoma
Drugs Dosage Remarks
Cotrimoxazole Trimethoprim 800mg and sulfamethoxazole 160mg once or twice daily First-line drug against all organisms causing actinomycetoma, drug of choice for nocardial infection
Amikacin 15mg/kg once daily intravenously Effective against Streptomyces somaliensis, Nocardia asteroides and N otitidiscaviarum. Not cost effective
Gentamicin 80mg twice daily intravenously or intramuscularly Amikacin is replaced with gentamicin because it is cost effective and easily available
Doxycycline 200mg once daily Effective against all the organisms causing actinomycetoma
Amoxycillin plus clavulanate Amoxicillin 875mg plus clavulanate 125mg twice daily orally Effective against N brasiliensis
Imipenem 1.5g once daily intravenously Effective against N asteroides; N otitidiscaviarum is resistant. Not cost effective
Ciprofloxacin 500mg twice daily orally N asteroides and N brasiliensis are resistant; Notitidiscaviarum is sensitive
Rifampicin 600mg once daily orally Most effective antibiotic against S somaliensis
Dapsone 100mg twice daily orally Effective against all the organisms causing actinomycetoma
Linezolid 600mg twice daily Effective against Nocardia spp.
Streptomycin 14mg/kg intramuscularly daily Effective against all the organisms causing actinomycetoma. Not preferred nowadays

Long duration of therapy, for 6 months to 2 years, is usually required for complete resolution of disease. In resistant and severe cases, newer agents like broad spectrum oxazolidinones (linezolid) and carbapenem (imipenem) are effective. It is recommended to continue therapy for the same period as was required to achieve the clinical and microbiologic cure. Change in therapy is considered if there is no response even after 3 weeks.

With availability of effective therapeutic regimens, it is now possible to obtain excellent response within a short period of time (Table IV). The success rate of therapy ranges from 60% to 90%.

Table IV.

Therapeutic regimmens used n the treatment of actinomycetoma
Regimen Intensive phase Maintenance Phase
Welsh regimen Amikacin 15mg/ kg/ day intravenous 12th hourly for 21 days (one cycle), 1 to 3 cycles with an interval of 15 days Cotrimoxazole (double strength) twice daily continuously (from first day of therapy) for 35 to 105 days
Modified Welsh regimen Amikacin 15mg/ kg/ day intravenous 12th-hourly for 21 days (one cycle), 3 to 4 cycles with an interval of 15 days Cotrimoxazole (double strength) twice daily and rifampicin 10mg/kg/day continuously (from first day of therapy) for 3 months after the last cycle
Two-step regimen Intravenous crystalline penicillin 1 MU every sixth hour, Intravenous gentamycin 80mg 12-hourly daily, cotrimoxazole 80/400 2 tablets twice daily orally for 5 to 7 weeks Amoxicillin 500mg three times daily orally and cotrimoxazole as in the intensive phase given for 2 to 5 months after complete inactivity (usually 6 to 16 months)
Modified two-step regimen Gentamycin 80mg intravenous 12th-hourly, and cotrimoxazole (double strength) two tablets twice daily continuously for 4 weeks Doxycycline 100mg and cotrimoxazole (double strength) two tablets twice daily orally for 5 to 6 months after the complete healing of sinuses
  • Eumycetoma

Surgery is the treatment of choice if the lesion is small enough for total excision. Early diagnosis and surgical resection with a wide margin of uninfected tissue prior to bone involvement results in the most successful outcome. The currently recommended approach is surgical debulking along with antifungal therapy for all cases of eumycetoma.

Except ketoconazole, other antifungal agents (Table V) demonstrate conflicting therapeutic responses. They are either ineffective in vivo or show initial favorable response followed by relapse after stopping the drug. Duration of antifungal therapy ranges from 18 to 24 months. The relapse rate ranges from 20% to 90%. Amputation and radical surgery are reserved for advanced cases with extensive bone involvement. Such patients require prostheses and rehabilitation.

Table V.

Drugs used in the treatment of eumycetoma
Drugs Dosage Remarks
Ketoconazole 200 to 400mg once daily orally Most effective antifungal agent
Itraconazole 300 to 400mg once daily orally Effective against Acremonium spp, Aspergillus spp and Fusarium spp
Voriconazole 400 to 600mg once daily orally Newer broad-spectrum triazoles with high tolerability and efficacy against Madurella spp. and Scedosporium apiospermum, but not cost-effective and are not available in endemic areas
Posaconazole 800mg once daily orally Same as voriconazole
Terbinafine 500mg twice daily orally Relatively effective against M mycetomatis and Leptospheria senegalensis
Liposomal amphotericin-B 3mg/kg daily intravenously in divided doses with an average total dose of 3.5g Initially effective with subsequent treatment failure

Patient Management

  • Patient follow-up

Frequent follow-up is necessary, at least once a month, to monitor response to therapy and side effects of drugs. Various imaging modalities and serologic tests (see above) can be employed to assess disease progression and response to therapy. The following clinical features suggest a good response:

  • Regression of edema and tenderness

  • Reduction in amount of discharge and grains

  • Closure and drying up of sinuses

Unusual Clinical Scenarios to Consider in Patient Management

Some of the drugs used for treatment such as dapsone, rifampicin and streptomycin are also used in tuberculosis and leprosy; hence, in patients with concomitant actinomycetoma and tuberculosis or leprosy these drugs are preferred over the others. Concomitant occurrence of mycetoma and human immunodeficiency virus (HIV) infection is likely to be coincidental.

Paradoxical reaction (i.e., initial worsening of disease following treatment) has been reported in a patient with mycetoma caused by Scedosporium apiospermum treated with posaconazole. The occurrence of paradoxical reaction represents the earliest marker of therapeutic efficacy.

What is the Evidence?

McGinnis, MR. "Mycetoma". Dermatol Clin. vol. 14. 1996. pp. 97-104.

(In this issue of Dermatology Clinic dedicated to "Cutaneous Mycology," the author provides an excellent review of fungal mycetoma with particular reference to history and clinical nomenclature, epidemiology, etiology, pathogenesis and host-pathogen interaction.)

Khatri, ML, Al-Halali, HM, Khalid, MF, Saif, SA, Vyas, MCR. "Mycetoma in Yemen: clinicoepidemiological and histopathologic study". Int J Dermatol. vol. 41. 2002. pp. 586-93.

(The clinical profile, histopathologic features, radiologic features, and response to various treatment regimens have been reported in 50 cases of eumycetoma and 20 cases of actinomycetoma.)

Mahagoub, AS, Mandell, GZ, Bennett, JE, Dolin, R. "Agents of mycetoma". Principles and practice of infectious diseases. Churchill Livingstone. 1995. pp. 2327-30.

(The author, who is the authority in mycetoma, has written a concise but very informative chapter on mycetoma with important practical tips on collection and processing of specimen.)

Ragunatha, S, Anitha, B, Inamadar, AC, Sacchidanand, S. "Fungal infections". Textbook of pediatric dermatology. JayPee Brothers Medical Publishers Pvt. Ltd. 2009. pp. 165-84.

(Though mycetoma is rare in children, the authors in the chapter on childhood fungal infections describe the differentiation between actinomycetoma and eumycetoma in an informative table.)

Palit, A, Ragunatha, S, Inamadar, AC. "Actinomycetoma: dramatic response to modified two-step regimen". Int J Dermatol. vol. 50. 2011. pp. 446-9.

(In a well-constructed case report of culture-negative actinomycetoma with excellent response to modified two-step regimen, the authors explain the rationale of modified two-drug regimen. The approach to a patient with actinomycetoma in a resource-poor set-up lacking modern diagnostic facilities is also addressed. The article underlines the importance of considering epidemiologic characteristics of mycetoma in starting empirical therapy.)

Ameen, M, Arenas, R. "Developments in the management of mycetomas". Clin Exper Dermatol. vol. 34. 2008. pp. 1-7.

(In this excellent review article on management of mycetoma, various drugs and regimen used in the management of actinomycetoma and eumycetoma are tabulated along with the references. Authors also give brief account on advances in diagnostics and prognostics mycetoma.)

Maiti, PK, Ray, A, Bandyopadhyay, S. "Epidemiological aspects of mycetoma from a retrospective study of 264 cases in West Bengal". Trop Med Int Health. vol. 7. 2002. pp. 788-92.

(In this largest epidemiologic study on mycetoma, the authors demonstrate the effect of geographic area, occupation, gender and site of involvement on the prevalence of organisms causing mycetoma.)

Liu, A, Maender, JL, Coleman, N, Hsu, S, Rosen, T. "Actinomycetoma with negative culture: A therapeutic challenge". Dermatol online J. vol. 14. 2008. pp. 5.

(The reasons for culture negativity are explained in this article. In addition, a brief account on use of histopathology, serodiagnosis and radiologic methods in identifying the organisms is also presented. The authors have recommended empirical therapy based on clinical and histopathologic findings.)

Brown-Elliot, BA, Brown, JM, Conville, PS, Wallace Jr, RJ. "Clinical and laboratory features of Nocardia spp. based on current molecular taxonomy". Clin Microbiol Rev. vol. 19. 2006. pp. 259-82.

(In this excellent review article, susceptibility pattern and laboratory evaluation of pathogenic Nocardia spp, including those causing mycetoma, are described. Six drug susceptibility patterns have been described, which can be used as guides in the selection of a therapeutic agent.)

Shawar, RM, Moore, DG, Larocco, MT. "Cultivation of Nocardia s pp. on chemically defined media for selective recovery of isolates from clinical specimens". J Clin Microbiol. vol. 28. 1990. pp. 508-12.

(The article gives solution to the problem of growing Nocardia spp in culture media. The study demonstrates that the isolation of Nocardia spp and Streptomyces spp can be enhanced by paraffin baiting. The organisms selectively metabolize paraffin and showed enhanced growth on paraffin-based agar when compared with blood agar.)

Ramam, M, Garg, T, D' Souza, P, Verma, KK, Kaitan, BK, Singh, MK. "A two-step schedule for the treatment of actinomycotic mycetomas". Acta Dermatol Venereol. vol. 80. 2000. pp. 378-80.

(The authors have proposed a regimen consisting of an intensive phase and a maintenance phase for the treatment of actinomycetoma in developing countries. Easily available and cost-effective drugs were administered. All the patients showed rapid clinical response during intensive phase of therapy.)

Fahal, A, Mahgoub El, S, El Hassan, AM, Jacoub, AO, Hassan, D. "Head and neck mycetoma: The mycetoma research centre experience". PLoS Negl Trop Dis. vol. 9 . 2015. pp. e0003587.

(In this article from the Mycetoma Research Centre, Sudan, significance of head and neck mycetoma regarding epidemiology, clinical manifestations, complications, and response to therapy is discussed.)

Beroud, G, Desbois, N, Coyo, C. "Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment". Infect Dis. vol. 47. 2015. pp. 830-3.

Verwer, PE, Notenboom, CC, Eadie, K, Fahal, AH, Verbrugh, HA, Van de Sande, WW. "A polymorphism in the chitotriosidase gene associated with risk of mycetoma due to Madurella mycetomatis mycetoma--A retrospective study". PLoS Negl Trop Dis. vol. 9 . e0004061.

(The relationship between SNP in the chitotriosidase enzyme and risk of mycetoma due to M. mycetomatis is demonstrated.)

Van de Sande, WW, Erasmus, MC, Fahal, AH. "Merits and pitfalls of currently used diagnostic tools in mycetoma". PLoS Negl Trop Dis. vol. 8 . 2014. pp. e2918.

(The article summarizes the merits and demerits of various diagnostic methods used in the identification of causative agents of mycetoma and extent of disease.)

Mhmoud, NA, Fahal, AH, van de Sande, WW. "The association between the interleukin-10 cytokine and CC chemokine ligand 5 polymorphisms and mycetoma granuloma formation". Med Mycol. vol. 51 . 2013. pp. 527-33.

Fahal, A, Mahgoub El, S, El Hassan, AM, Abdel-Rahman, ME. "Mycetoma in the Sudan: an update from the Mycetoma Research Centre, University of Khartoum, Sudan". PLoS Negl Trop Dis. vol. 9 . 2015. pp. e0003679.

(The article from the Mycetoma Research Center shows various epidemiological features of a large number of patients presenting with mycetoma.)

Zein, HA, Fahal, A, Mahgoub El, S, El Hassan, AM. "Predictors of cure, amputation and follow-up dropout among patients with mycetoma seen at the Mycetoma Research Centre, University of Khartoum, Sudan". Trans R Soc Trop Med Hyg. vol. 106. 2012. pp. 639-44.

Dupont, B, Datry, A, Poirée, S, Canestri, A, Boucheneb, S, Fourniols, E. "Role of a NSAID in the apparent cure of a fungal mycetoma". J Mycol Med. 2016.

(The role of NSAIDs as adjuvant therapy in the management of mycetoma is discussed.)
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