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Treating Rare Fungal Infections: Maduromycosis

Treating Rare Fungal Infections: Maduromycosis

This feature series was taken from the 4th annual postgraduate course and workshop in medical mycology-dermatomycology from July 27-30, 1979 in Newport Beach, CA. This article concludes the series. Download the PDF to view the tables. 

Dr. Graham was the former head of dermatopathology at the Armed Forces Institute of Pathology and the former chair of dermatology at UC Irvine in Irvine, CA. He has made available his personal library of kodachromes, slides and lectures collected throughout his career with a generous donation to the Wake Forest University Baptist Medical Center Library. Dr. Graham’s lectures and personal images in dermatomycology will be highlighted in this series to refresh the practicing clinician on deep cutaneous mycotic disease.

Maduromycosis, also known as mycetoma, is a progressive granulomatous infection involving the skin and subcutaneous tissues with potential to invade muscle and bone.1,2 The term mycetoma means “fungal tumor” in Greek,1 but causative organisms can be fungal or bacterial. Maduromycosis due to fungi is otherwise called eumycetoma, and is caused by the species Madurella, Pseudallescheria, Acremonium and Leptosphaeria as well as dermatophytes.1,2 Actinomycetoma secondary to filamentous bacteria are known to be caused by Nocardia, Actinomadura, Actinomyces and some Streptomyces species.1,2 The first medical description of maduromycosis was given by Gill in 1842, whose index patient in Madura region of India gave us the term Madura foot.3  

fungal

 

Figure 1: Mycetoma, causative organism Actinomadura madurae. Note the multiple nodules in the tissue. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology

Epidemiology And Pathogenesis

Arid geographic regions have the highest incidence of maduromycosis, including regions of India,  Africa and North and South America.2 Mexico is the country with the highest incidence of this infection in the Americas, followed by Venezuela and Argentina.2 While uncommon in the United States, a number of cases have been sporadically reported across the northeast, southeast and midwest.4 Maduromycosis typically arises due to traumatic inoculation of organisms into the skin and subcutaneous tissues, where the organisms continue to grow. Progression of infection into muscle and bone may follow if untreated, and involvement may be acute or chronic, sometimes enduring for years.1 Actinomycetoma tends to progress more rapidly than eumycetoma.5 Due to the mechanism of infection, the condition is most likely in populations who walk barefoot without proper footwear and have acquired minor trauma, facilitating organism entry.5 Men age 20 to 50 are most commonly affected.5 Malnutrition and immunosuppression may also be predisposing factors.1,5

Clinical Presentation 

The classic presentation of maduromycosis is the so-called Madura foot, although other areas such as the hand or arm may be affected.1,5 When arising in the foot, the typical initial area of involvement is either the instep or the webs of the toes.2  The initial manifestation of infection is an asymptomatic papule. As the infection progresses to include subcutaneous tissues, asymptomatic to minimally painful diffuse soft tissue swelling is often noted, followed by the formation of nodules (Figure 1) and purulent drainage of granules from sinus tracts formed by the organism (Figure 2).1,2,5 

fig 2

Figure 2. Mycetoma, causative organism Nocardia brasiliensis. Note the muliple sinus tracts producing exudate.Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology

These granules are themselves conglomerations of organism colonies, and may be visible even without microscopy.1,5 Infection of bone or muscle may then ensue. Presentation is similar for both actinomycetoma and eumycetoma. The presence of characteristic granules, along with sinus tract formation and tissue swelling are the hallmarks of clinical diagnosis for this condition.2 In some cases, systemic spread of the causative organism is possible even in immunocompetent patients, particularly with the rapidly progressive actinomycetoma.5 Bacterial superinfection is also a possibility, and can potentially lead to sepsis.5

Histopathology 

Histopathologic examination of mycetoma tissue specimens often reveals granulomatous inflammation (Figure 3) and fibrosis involving abscesses that contain the causative organism’s characteristic granules.1,5

fig 3

Figure 3. Histologic section of mycetoma caused by Nocardiabrasiliensis demonstrating granulomatous inflammation and mixed cellular infiltrate. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology

Different organisms tend to present with different colored granules, as noted in Table 1. In eumycetoma, a number of inflammatory cells may also be present, including lymphocytes, plasma cells, eosinophils and macrophages.5 The cellular infiltrate of an actinomycetoma is similarly mixed (Figure 4).  

fig 4

Figure 4. Histologic section of mycetoma caused by Nocardia brasiliensis, high magnification. Note the cellular infiltrate largely composed of lymphocytes and neutrophils, with scant eosinophils. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology

Differential Diagnosis 

While history and physical exam can aid in diagnosis, it is important to distinguish mycetoma from potentially similarly presenting conditions, including actinomycosis, blastomycosis, coccidioidomycosis, leishmaniasis, yaws, syphilis and chronic osteomyelitis.1,5  

Diagnostic Tests

Information obtained in the history and physical can be augmented by microscopic evaluation of biopsy specimens and exudate, demonstrating characteristic granules of the causative organism.2 Potassium hydroxide (KOH) and Gram stain of the exudate can be helpful in delineating whether the causative organism is fungal or bacterial.1 Cultures of the specimen or exudate on Sabouraud agar (for fungal causes) and brain-heart infusion agar, blood agar, mannitol salt agar or MacConkey agar (for actinomycetoma) provides the ultimate diagnosis of the specific causative organism.2,5 Microscopically, perithecia and spores may be seen in samples from an eumycetoma.

Imaging is often indicated to ascertain degree of bony involvement. Plain radiographs may show there is some degree of bony involvement, sometimes with a periosteal reaction similar to that of osteosarcoma.5 Magnetic resonance imaging shows a characteristic “dot in circle” sign due to an effect of the imaging technique on the granules.2,6 Ultrasound may also sometimes be performed, visualizing the granules which are hypereflective.5 

Treatment

Treatment of maduromycosis depends on the causative organism (Table 2). Eumycetomas should ideally be surgically removed prior to onset of bony involvement.1,2 Eumycetomas are frequently encapsulated, and care should be taken not to rupture the capsule, as this may lead to organism spread and mycetoma recurrence.5 Surgery may be curative, or may be followed by or performed in conjunction with systemic antifungal therapy.1,2 Antifungal options include itraconazole, posaconazole, fluconazole, ketoconazole and terbinafine, often given for a period of years.1,2,5

Actinomycetomas may respond to antibiotic therapy alone, but can require surgical intervention in severe cases.2 There is no sole consensus on antibiotic therapy for actinomycetomas. Antibiotics described in the literature include penicillin (specific to A israelii infection), sulfonamides, aminoglycosides with trimethoprim-sulfamethoxazole or dapsone, rifampicin with co-trimoxazole and imipenem, depending on the organism implicated and clinical response.1,2,7,8 Antibiotic therapy is best continued until there is clinically a resolution of the mycetoma, ideally with radiologic and serologic evidence that the organism has been eradicated. This may take up to, but rarely beyond, a year of antibiotic therapy in most patients.5

Key Points

• Maduromycosis is a progressive granulomatous infection of the skin and subcutaneous tissues, and may progress to involve muscle and bone.

• Causes may be fungal (in the case of eumycetoma) or filamentous bacteria (actinomycetoma), but both present clinically similarly. 

• The Madura foot is the classic presentation of maduromycosis, but other sites may be involved.

• Major clinical findings indicative of maduromycosis include soft tissue swelling, sinus tract formation and characteristic pigmented granules of the causative organism. Histologic findings include granulomatous inflammation, fibrosis and presence of the aforementioned granules on microscopy.

• KOH and Gram stain of the exudate may aid in diagnosis of the etiologic cause, along with culture of the causative fungus or filamentous bacteria.

• Treatment for eumycetoma is primarily surgical, and often combined with antifungal agents such as itraconazole, fluconazole and posaconazole.

• Treatment for actinomycetoma is primarily medical, with antibiotics such as sulfonamides, aminoglycosides or carbapenems, among others. There is no sole consensus on ideal antibiotic therapy, but it should be tailored to the causative organism and clinical response. Surgery may be indicated in severe cases. n

Ms. Landis is with the Center for Dermatology Research, department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.

Mr. Al-Dabagh is a 4th year medical student at Case Western Reserve University School of Medicine in Cleveland, OH. 

Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.

Disclosures: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol-Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol-Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research. 

Ms. Landis and Mr. Al-Dabagh have no conflicts to disclose.

References

1. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2nd ed. St. Louis, MO: Mosby; 2008.

2. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2011.

3. Chalmers AJ, Archibald RG. A Sudanese maduromycosis. Ann Trop Med Parasitol. 1916;10:169-222.

4. Warintarawej A, Winter WG Jr Goodman NL. Maduromycosis (Madura Foot) in Kentucky. South Med J. 1975;68(12):1570-1575.

5. Venkatswami S, Sankarasubramanian A, Subramanyam S. The madura foot: looking deep. Int J Low Extrem Wounds. 2012;11(1):31-42.

6. Sarris I, Berendt AR, Athanasous N, Ostlere SJ. MRI of mycetoma of the foot: two cases demonstrating the dot-in-circle sign. Skeletal Radiol. 2003;32(3):179-83.

7. Ameen M, Arenas R, Vásquez del Mercado E, Fernández R, Torres E, Zacarias R. Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulfonamides. J Am Acad Dermatol. 2010;62(2):239-246.

8. Joshi R. Treatment of actinomycetoma with combination of rifampicin and co-trimoxazole. Indian J Dermatol Venereol Leprol. 2008;74(2):166-168.

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