Mycetoma: eumycetoma and actinomycetoma

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Mycetoma

eumycetoma and actinomycetoma

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Mycetomas (Madura foot) are endemic in the tropics and sub-tropics. They are chronic, granulomatous, subcutaneous infections caused by either actinomycetes bacteria or eumycetes fungi, giving rising to actinomycetomas and eumycetomas, respectively. The infectious agents are saprophytes existing in soil or plants, and infection usually results from traumatic inoculation into the skin. Consequently, the disease most commonly affects agriculturalists and those who are bare-foot. The disease is characterized by abscesses, draining sinuses and discharging grains, and it slowly progresses with risks of bone and visceral involvement. The discharging grains represent aggregates of fungal hyphae or bacterial filaments. Actinomycetomas are produced by agents of the genera Nocardia, Actinomadura, Streptomyces and Nocardiopsis. Nocardia is the commonest agent, particularly in the Americas, but Streptomyces somaliensis is more common in Sudan and the Middle East. Eumycetomas are caused by a large number of fungi: Madurella mycetomatis is of particular significance as it is the most prevalent causative agent in regions of India and Africa.

Management strategy

Treatment of mycetomas is generally difficult, and management varies from a very conservative approach to chemotherapy and surgery. Effective chemotherapy is available for actinomycetomas. However, eumycetomas are more refractory to drug therapy.

Eumycetomas may sometimes be managed conservatively as they are usually indolent and seldom life threatening. Treatment is then symptomatic with relief of pain and applications of dressings to affected areas, particularly the sinuses. Any secondary bacterial infection requires treatment. More active management consists of long courses of antifungals, 18–24 months or even longer, together with aggressive surgical excision and debulking. Antifungal therapy is initiated before surgery and continued afterwards to reduce the risk of recurrence. Small lesions have a more favorable prognosis as they are more easily excised completely. Advanced disease with bony involvement characteristically shows poor therapy response, and often requires surgical amputation. Of all the antifungal drugs, azoles have been most commonly used. Fluconazole has been found to be ineffective but ketoconazole and itraconazole have both demonstrated efficacy, particularly at high doses (200–400 mg daily for ketoconazole and 300–400 mg daily for itraconazole). Itraconazole is preferred as it is better tolerated for longer periods of time and is thought to demonstrate greater efficacy than ketoconazole, although there are no published studies comparing their efficacy.

There are reports of the high tolerability and efficacy of the newer broad-spectrum triazoles such as voriconazole and posaconazole against Madurella species and Scedosporium apiospermum infection. This is supported by in vitro susceptibility testing. However, their high costs are prohibitive for use in most endemic regions. Griseofulvin appears to be ineffective. Amphotericin has shown variable responses in the few cases that it has been used in. High-dose terbinafine (500 mg twice daily) has demonstrated limited clinical efficacy that correlates with in vitro susceptibility testing which has shown only moderate efficacy of terbinafine against some black grain mycetomas. In vitro studies have not demonstrated any efficacy of echinocandins against Madurella mycetomatis.

Actinomycetomas are usually amenable to antibiotic therapy, but cure rates vary widely from 60% to 90%. Combined drug therapy is preferred in order to prevent the development of drug resistance as well as to eradicate any residual infection. The duration of drug therapy depends on clinical response. Cure is defined by a lack of clinical activity, absence of grains and negative cultures. Treatment with sulfonamides and sulfonamide combinations such as trimethoprim–sulfamethoxazole (co-trimoxazole) are usually first line. Aminoglycosides, tetracyclines, rifampicin, ciprofloxacin and amoxicillin-clavulanate have also been successfully used. Parenteral amikacin and oral co-trimoxazole combination therapy is especially advocated for cases at risk of bone or visceral involvement. Actinomycetomas seldom require surgical management.

Specific investigations

It is imperative to differentiate between eumycetomas, which respond poorly to chemotherapy, and actinomycetomas, which generally respond well. Furthermore, species identification is important as it has treatment and prognostic implications, some species having demonstrated higher efficacy to some chemotherapy regimens than others.

The clinical diagnosis can be confirmed by the demonstration and identification of grains, which can be obtained by direct extraction, fine needle aspiration, or deep tissue biopsy. Direct microscopy of a crushed grain in 20% potassium hydroxide gives an indication of the size and shape of the grain, which provides an initial clue to the causative agent, whether bacterial or fungal. Histopathology of a deep surgical biopsy demonstrates a granulomatous, inflammatory reaction with abscesses containing grains. Culture of grains using Sabouraud or blood agar media permits species identification. However, fungal culture can be particularly difficult, as morphological differentiation of fungi may be poor or delayed. Molecular tests have therefore been developed for species identification of several black-grained eumycetomas, including species-specific polymerase chain reaction (PCR) analysis. Serological tests such as enzyme-linked immunosorbent assay (ELISA) are employed by some centers to support diagnosis as well as to assess therapy response. Radiology and ultrasound enable assessment of disease extent and bony involvement. Helical computed tomography can provide detailed assessments of soft tissue and visceral involvement.

First-line therapies

image Sulfonamides B
image Aminoglycosides B
image Itraconazole C

A modified two-step treatment for actinomycetoma.

Ramam M, Bhat R, Garg T, Sharma VK, Ray R, Singh MK, et al. Indian J Dermatol Venereol Leprol 2007; 73: 235–9.

The authors emphasise that, although parenteral therapy regimes demonstrate high efficacy, they are costly in terms of inpatient stays. They describe a reduced parenteral regime (intravenous gentamicin 80 mg twice daily together with oral co-trimoxazole 320/1600 mg twice daily for 1 month), followed by a longer phase of oral medication (doxycycline 100 mg twice daily together with co-trimoxazole at the same dose). All 21 patients demonstrated significant clinical response at the end of the parenteral phase of treatment. The oral phase needed to be continued for 3.5–16 months (mean 9.1 months) until cure, and in the majority of these patients this included a treatment period of 5 to 6 months after complete healing of the lesions to prevent any relapse.

The safety and efficacy of itraconazole for the treatment of patients with eumycetoma due to Madurella mycetomatis.

Fahal AH, Rahman IA, El-Hassan AM, Rahman ME, Zijlstra EE. Trans R Soc Trop Med Hyg 2011; 105: 127–32.

This prospective study of 13 patients demonstrated that pre-operative treatment with a 1-year course of itraconazole enhances lesion encapsulation that facilitates wide local excision avoiding unnecessary mutilating surgery. Itraconazole was given at 400 mg daily for 3 months followed by a reduced dose of 200 mg daily for 9 months. All patients showed a good clinical response to the 400 mg daily dose but a slower response to the 200 mg daily dose. Post-treatment surgical exploration demonstrated that all lesions were well localized and encapsulated and easily removed. There was only a single recurrence after a follow-up period of 18–36 months.

Second-line therapies

image Amoxicillin–clavulanate B
image Terbinafine B
image Ketoconazole C
image Posaconazole D
image Imipenem D
image Voriconazole E
image Oxazolidinones E

Ketoconazole in the treatment of eumycetoma due to Madurella mycetomii.

Mahgoub ES, Gumaa SA. Trans R Soc Trop Med Hyg 1984; 78: 376–9.

This trial consisted of 13 patients treated in the Sudan and Saudi Arabia. Ketoconazole was given at doses of 200–400 mg daily for three to 36 months (median 13 months). Treatment was well tolerated. Five patients were cured, and a further four improved. Response appeared to be dose-dependent. The authors recommend a 400 mg daily dose of ketoconazole, and a minimum treatment period of 12 months where there is bony involvement irrespective of clinical improvement.

Given the availability of newer antifungals, there are few recent trials evaluating the use of ketoconazole for eumycetomas. However, it is a less expensive drug than itraconazole and therefore is more commonly used in endemic regions.

Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulphonamides.

Ameen M, Arenas R, Vásquez del Mercado, Torres E, Zacarias R. J Am Acad Dermatol 2010; 62: 239–46.

Eight patients with severe and protracted infection (two with visceral and a further two with bone involvement) refractory to previous sulfonamide monotherapy received a 3-week course of parenteral imipenem (1.5 g daily, n=3) given as either monotherapy or in combination with amikacin (1 g daily, n=5). Treatment cycles were repeated at 6-month intervals. Oral co-trimoxazole was also given and continued between cycles. Treatment was well tolerated and four patients achieved clinical and microbiological cure after one to two cycles of treatment, the others demonstrating greater than 75% clinical improvement and negative culture results.

This study also demonstrated that sulfonamides are effective for limited disease of relatively short duration. Their partial efficacy in severe cases was the reason for continuing treatment with sulfonamides in combination with imipenem.

Third-line therapies

image Rifampicin C
image Amphotericin B D

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Mycetoma

eumycetoma and actinomycetoma

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Mycetomas (Madura foot) are endemic in the tropics and sub-tropics. They are chronic, granulomatous, subcutaneous infections caused by either actinomycetes bacteria or eumycetes fungi, giving rising to actinomycetomas and eumycetomas, respectively. The infectious agents are saprophytes existing in soil or plants, and infection usually results from traumatic inoculation into the skin. Consequently, the disease most commonly affects agriculturalists and those who are bare-foot. The disease is characterized by abscesses, draining sinuses and discharging grains, and it slowly progresses with risks of bone and visceral involvement. The discharging grains represent aggregates of fungal hyphae or bacterial filaments. Actinomycetomas are produced by agents of the genera Nocardia, Actinomadura, Streptomyces and Nocardiopsis. Nocardia is the commonest agent, particularly in the Americas, but Streptomyces somaliensis is more common in Sudan and the Middle East. Eumycetomas are caused by a large number of fungi: Madurella mycetomatis is of particular significance as it is the most prevalent causative agent in regions of India and Africa.

Management strategy

Treatment of mycetomas is generally difficult, and management varies from a very conservative approach to chemotherapy and surgery. Effective chemotherapy is available for actinomycetomas. However, eumycetomas are more refractory to drug therapy.

Eumycetomas may sometimes be managed conservatively as they are usually indolent and seldom life threatening. Treatment is then symptomatic with relief of pain and applications of dressings to affected areas, particularly the sinuses. Any secondary bacterial infection requires treatment. More active management consists of long courses of antifungals, 18–24 months or even longer, together with aggressive surgical excision and debulking. Antifungal therapy is initiated before surgery and continued afterwards to reduce the risk of recurrence. Small lesions have a more favorable prognosis as they are more easily excised completely. Advanced disease with bony involvement characteristically shows poor therapy response, and often requires surgical amputation. Of all the antifungal drugs, azoles have been most commonly used. Fluconazole has been found to be ineffective but ketoconazole and itraconazole have both demonstrated efficacy, particularly at high doses (200–400 mg daily for ketoconazole and 300–400 mg daily for itraconazole). Itraconazole is preferred as it is better tolerated for longer periods of time and is thought to demonstrate greater efficacy than ketoconazole, although there are no published studies comparing their efficacy.

There are reports of the high tolerability and efficacy of the newer broad-spectrum triazoles such as voriconazole and posaconazole against Madurella species and Scedosporium apiospermum infection. This is supported by in vitro susceptibility testing. However, their high costs are prohibitive for use in most endemic regions. Griseofulvin appears to be ineffective. Amphotericin has shown variable responses in the few cases that it has been used in. High-dose terbinafine (500 mg twice daily) has demonstrated limited clinical efficacy that correlates with in vitro susceptibility testing which has shown only moderate efficacy of terbinafine against some black grain mycetomas. In vitro studies have not demonstrated any efficacy of echinocandins against Madurella mycetomatis.

Actinomycetomas are usually amenable to antibiotic therapy, but cure rates vary widely from 60% to 90%. Combined drug therapy is preferred in order to prevent the development of drug resistance as well as to eradicate any residual infection. The duration of drug therapy depends on clinical response. Cure is defined by a lack of clinical activity, absence of grains and negative cultures. Treatment with sulfonamides and sulfonamide combinations such as trimethoprim–sulfamethoxazole (co-trimoxazole) are usually first line. Aminoglycosides, tetracyclines, rifampicin, ciprofloxacin and amoxicillin-clavulanate have also been successfully used. Parenteral amikacin and oral co-trimoxazole combination therapy is especially advocated for cases at risk of bone or visceral involvement. Actinomycetomas seldom require surgical management.

Specific investigations

It is imperative to differentiate between eumycetomas, which respond poorly to chemotherapy, and actinomycetomas, which generally respond well. Furthermore, species identification is important as it has treatment and prognostic implications, some species having demonstrated higher efficacy to some chemotherapy regimens than others.

The clinical diagnosis can be confirmed by the demonstration and identification of grains, which can be obtained by direct extraction, fine needle aspiration, or deep tissue biopsy. Direct microscopy of a crushed grain in 20% potassium hydroxide gives an indication of the size and shape of the grain, which provides an initial clue to the causative agent, whether bacterial or fungal. Histopathology of a deep surgical biopsy demonstrates a granulomatous, inflammatory reaction with abscesses containing grains. Culture of grains using Sabouraud or blood agar media permits species identification. However, fungal culture can be particularly difficult, as morphological differentiation of fungi may be poor or delayed. Molecular tests have therefore been developed for species identification of several black-grained eumycetomas, including species-specific polymerase chain reaction (PCR) analysis. Serological tests such as enzyme-linked immunosorbent assay (ELISA) are employed by some centers to support diagnosis as well as to assess therapy response. Radiology and ultrasound enable assessment of disease extent and bony involvement. Helical computed tomography can provide detailed assessments of soft tissue and visceral involvement.

Mycetoma.

Welsh O, Vera-Cabrera L, Salinas-Carmona MC. Dermatol Clin 2007; 25(2): 195–202.

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