Clinics in Dermatology (2007) 25, 195 – 202

Mycetoma
Oliverio Welsh, MDa,*, Lucio Vera-Cabrera, DrSca, Mario Cesar Salinas-Carmona, MDb
a
Dermatology Department, University Hospital, UANL, Monterrey, NL 64460, México
b
Immunology Department, Medical School, UANL, Monterrey, NL 64460, México

Abstract Mycetoma is a granulomatous infection affecting mainly the feet and lower extremities. It can
be caused either by aerobic, branched actinomycetes or by eumycetes. Most cases are found in tropical
and subtropical regions. The infection is usually produced by the introduction of the etiologic agents
through minor wounds caused by thorns and wood splinters. Clinically the disease begins as small, firm
nodules that can enlarge to form extensive lesions with fistulae and abscesses with pus containing
granules of the causative microorganisms. Antimicrobials and surgery are used in the management of
mycetoma. The actinomycetomas generally respond well to antimicrobials. For eumycetomas, surgery
may be required. New therapeutic options for drug-resistant cases are discussed.
D 2007 Elsevier Inc. All rights reserved.

Introduction Nocardia mexicana, Nocardia veterana, Nocardiopsis

Mycetoma is endemic in tropical and subtropical regions
of the world, predominating between latitudes 158S and
308N. Asia, India, the Yemen, and Pakistan have the highest
incidence. In Africa, mycetoma predominates in Sudan,
Somalia, Mauritania, Senegal, and their neighboring
countries. Mycetoma has the highest incidence in Venezuela
and Mexico on the American continent, but it can be found
in almost any Central and South American country.1-6
Worldwide, about 60% of cases are caused by actino-
mycetes; the rest are caused by true fungi. Mycetoma is 4
times more common in men. In Africa, eumycetomas are
more frequently observed than actinomycetomas, whereas
in India, actinomycetes are found in more than half of the
cases reported.
Species of the genera Nocardia, Streptomyces, and
Actinomadura are the major agents of actinomycetoma
and include some newly described species (see Table 1).
* Corresponding author.
E-mail address: owelsh@yahoo.com (O. Welsh).
dassonvillei, Rhodococcus spp, and Gordona terrae have
rarely been isolated.7,8
In Mexico, actinomycetes are the principle etiologic
agent, accounting for about 98% of the cases, Nocardia
brasiliensis being found in 86% of the infections.2 The
distribution of the infecting bacteria shows strong geo-
graphic variation. Actinomadura pelletieri is more common
in regions with more rainfall. Conversely, N brasiliensis and
Streptomyces somaliensis predominate in dry, desert areas.6
Eumycetoma is produced by a variety of fungi including
the genera Acremonium, Fusarium, Leptosphaeria, and
Madurella (see Table 2). Madurella mycetomatis is the most
frequently isolated organism causing eumycetoma in the
world, and in some countries like Sudan it is associated with
up to 70% of the cases.9
Clinical manifestations
The disease predominates in rural workers between 20
and 40 years of age. The microorganisms penetrate the
cutaneous and subcutaneous tissues through minor trauma,

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196 O. Welsh et al.

Table 1 Causative agents of actinomycetoma grouped by

characteristics—the size, shape and color of the granules—
appearance of typical intralesional grains can be indicative of the etiologic agent.
S somaliensis produce basophilic granules, without
Agents Color of grains
clubs, of approximately 200 to 800 lm in diameter, which
N asteroides White are surrounded by inflammatory cells. The granule is hard
N brasiliensis White such that cutting it with the microtome’s knife produces
Nocardia caviae White to yellow
several clefts. A pelletieri produces purplish-red granules,
Nocardia farcinica White to yellow
N transvalensis White
without clubs, and it can adopt the appearance of broken
N mexicana – dishes. Actinomadura madurae produces the largest gran-
N veterana – ules. These are soft, white-yellowish, and vary in size from
N dassonvillei Cream 1 to 5 mm in diameter. Histologically, the granules of A
A madurae White to yellow or pink madurae have an irregular outline and are deeply basophil-
A pelletieri Red ic. At the periphery these are surrounded by a lighter stained
A latina – band known as pseudoclubs (Fig. 3). N brasiliensis
S somaliensis Yellow to brown produces smaller granules 150 to 300 lm in diameter that
G terrae – are usually surrounded by a layer of clubs.
Eumycetic grains can usually be seen in the pus with the
naked eye. In tissue, they are seen as masses of entangled
although in some cases there is no history of previous injury. filaments of a dark or white color, 4 to 5 lm wide. They are
The infection causes an inflammatory reaction with the generally embedded in intercellular cement. In the periphery,
production of microabscesses. the hyphae adopt a vesicular form (Fig. 4). The color of the
Mycetoma begins as a small, hard tumefaction or nodule grains can vary from black, as in the case of M mycetomatis,
that evolves to form microabscesses that discharge a Madurella grisea, Pyrenochaeta romeroi, and others, to
serosanguinous, viscous, or purulent exudate via skin
fistulae (Fig. 1). The exudate contains granules of the
infecting organisms. Remarkably, even with extensive Table 2 Causative agents of eumycetoma grouped by
disease, neither pain nor systemic manifestations are usually appearance of typical intralesional grains
present. Respiratory, neurologic, or other symptoms, how- Agents Color of grains
ever, may be manifest when the disease affects the chest, Acremonium falciforme White
head, and neck, or spine. The invasion of the periosteum and Acremonium kilense White
adjacent bones may lead to osteomyelitis. Acremonium recifei White
Although mycetoma has been described as affecting Cylindrocarpon cyanescens White
mainly the lower extremities, it has also been found in many Cylindrocarpon destructans White
other regions of the body including the thorax, hands, Pseudallescheria boydii White
forearm, gluteus, knee, and head.1,2,4,10 In Mexico, the back Fusarium oxysoprum White
is the second most common site of lesion and is associated Fusarium solani White
Fusarium moniliforme White
with the transportation of logs on the backs of rural laborers.
Hormonema spp
In Sudan, the hands are the second most frequent location.
Aspergillus flavus Green
Actinomycetoma spreads slowly to adjacent areas, and, in Aspergillus nidulans White
some cases, it may propagate by lymphatic or hematologic Polcycytella hominis White
dissemination. Mycetoma affecting the back can spread to Trichophyton spp White
the vertebral bodies, producing compression of the spinal Microsporum spp White
cord and leading to paraplegia or other neurologic mani- Plenodomus avramii Black
festations depending on the site of the lesions. Corynespora cassiicola Black
Curvularia geniculata Black
Curvularia lunata Black
Histopathology Lepstosphaeria senegalensis Black
Lepstosphaeria thompkinsii Black
Histologically, the lesions reveal the presence of a Madurella grisea Black
granulomatous inflammatory reaction with abscesses con- Pseudochaetosphaeronema larense Black
Pyrenochaeta mackinnonii Black
taining granules of the infecting organism. The actino-
Pyrenochaeta romeroi Black
mycetic granules consist of masses of filaments embedded
Madurella mycetomatis Black
in a material known as intercellular cement. Sometimes the Neotestudina rosatii White
granules are surrounded by maze-shaped structures called Exophiala jeanselmei Black
clubs (Fig. 2). Despite the causative agent, the clinical Phialophora verrucosa Black
picture of mycetoma is quite similar; however, the histologic

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Mycetoma 197

yellow-white, as in Scedosporium apiospermum, Acremo-

nium kiliense, Fusarium solani, and others (see Table 2).

Laboratory diagnosis
Direct microscopic examination of the pus from the
lesions in the actinomycetomas with 10% KOH or saline
reveals the presence of granules (Fig. 2). The size, form, and
color, together with the presence or absence of clubs or
pseudoclubs gives a clue to the identity of the etiologic
agent. In the case of A madurae, the granules can be seen
without the aid of a microscope. In other species, the
granules are smaller. In the case of Nocardia spp, clubs are
frequently seen at the periphery.
Isolation of actinomycetes can be achieved by culture
of the pus, granules, or tissue samples using Sabouraud,
mycobiotic, or blood agar media. Colonies grow after 7
to 10 days of incubation at 358C to 378C. The firm
colonies have a folded, irregular surface. The colony color

Fig. 2 A, Granules of N brasiliensis. Direct microscopic

examination of the pus. B, Typical colonies of N brasiliensis on
Saboreaud agar.

can vary according to the species. Nocardial colonies are

Fig. 1 Mycetoma cases produced by N brasiliensis. A,
Inflammation of the dorsum of the foot and ankle showing
abscesses and sinuses. B, Mycetoma of the back of the neck.
usually chalky and can vary from white, yellow, or
orange in color. A madurae usually produces waxy
yellow-white or pink colonies. A pelletieri colonies are
usually red or purplish. S somaliensis produces yellow-
white or bluish colonies.
Identification of the infecting species is made by several
biochemical tests including casein hydrolysis, gelatin
liquefaction, and decomposition of substrates, eg, hypo-
xantine, tyrosine, adenine, and xanthin.11 More recently,
API 32C (BioMérieux, Marcyl dEtoile-France) has been
used for identification of microorganisms.12 Mycolic acid
analysis of the cell wall has also been used for the
identification of Nocardia and other related genera con-
taining mycolic acids.13 When these tests are not conclu-
sive, the use of nucleotide sequencing analysis of the small
ribosomal subunit gene (16sRNA) or a part of the 65-kDa
heat shock protein gene has been used to define the identity
of the actinomycete. This methodology has permitted the
identification of new species of Nocardia and Actino-
madura, including N veterana, N mexicana, and Actino-
madura latina as causative agents of actinomycetoma.14-16

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198 O. Welsh et al.

An enzyme-linked immunosorbent assay test for

N brasiliensis, which detects antibodies against a 24- to
26-kDA antigen, can be used to confirm the diagnosis if this
organism is suspected.17
Based on the color of the grains, the morphology of the
fungal colony, and the microscopic characteristics of their
sexual and asexual stages, the laboratory can define the
etiologic agent of the mycetoma. Some fungal isolates
require physiologic tests for the species identification. In
cases where identification cannot be determined, molecular
tests such as amplification of the ribosomal gene complex,
including the 28S ribosomal subunit and intergenic regions,
can be used.18
To date, a reliable and specific serologic test for the
diagnosis of eumycetoma has not been developed.
Imaging studies, including X-rays, tomography, ultraso-
nography, and magnetic resonance imaging, are all useful to
determine the extension of the lesions in bone, organ, and
neighboring tissues.19-21 Imaging studies are also useful in
monitoring the response to therapy.

Fig. 4 A, Eumycetoma of the foot produced by M mycetomatis.

B, Detail of the grain of this fungus showing entangled masses of
dark hyphae. Hematoxylin-eosin stain.

In cases of actinomycetoma recalcitrant to treatment, an

evaluation of the antimicrobial susceptibility of the
causative bacteria or fungus is necessary to determine
the best alternative therapy. An underlying cellular or
humoral immunodeficiency should also be screened for in
such patients.

Host response to mycetoma agents

Fig. 3 A, Histophathologic characteristics of A pelletieri. Red
purplish granules with the appearance of broken dishes. B,
Microscopic appearance of A madurae granule.
Role of innate immunity
Although many people are exposed to etiologic agents
causing mycetoma, few develop the disease. The role of
innate immunity in host resistance to mycetoma-producing
fungi and bacteria has been studied in vitro and in animal
models, but few studies have been performed in humans.
Local host response, characterized by neutrophil chemotaxis
and small vessel congestion, is initially nonspecific. Later,
macrophages and monocytes present at the site of infection.
Activated by the cytokines interferon c and tumor necrosis
factor a, these cells have enhanced microbiocidal activity.

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Mycetoma
Some pathogenic bacteria, eg, Nocardia asteroides, are
more virulent in the log growth phase because of the
induction of high levels of catalase. Another factor,
superoxide dismutase, is also thought to play a role in
its pathogenesis.
In 1978, Melendro et al22 infected mice with Listeria
monocytogenes and N brasiliensis and found that cross-
protection against these microorganisms was associated with
activation of macrophages. Using N asteroides, Beaman
et al23 found that virulent bacteria in the log growth phase
may escape oxygen-dependent microbiocidal effectors and
continue to multiply within the phagocytic cells. Although
these results support the important role played by these cells
in host resistance to infection, additional human studies are
needed to understand the role of cytokines in the innate
immunity to mycetomal agents.
Role of T-cell lymphocytes and cell-mediated
immunity
Adaptive immunity differs from innate immunity be-
cause it is specific, inducible, transferable, and has memory.
These features represent the hallmark of acquired or
adaptive immunity. The role of B and T lymphocyte effector
cells in nocardial infection has been studied in animals.
Nude mice, which are athymic animals deficient in T
lymphocytes, are susceptible to infection with N asteroides
and develop a lethal infection unlike their heterozygous
(nude/+) littermates (which carry only part of the T-cell
defect)24 and present a local reaction to challenge with
Nocardia antigen but do not die of a systemic infection.
This has also been observed with N brasiliensis using an
athymic rat model of infection.25
The role of T cells in host resistance to Nocardia
infection is in part mediated by macrophages activated by
cytokines. Based on this and other findings, it is accepted
that cell-mediated immune response is responsible for host
protection in intracellular pathogens such as L monocyto-
genes, Mycobacterium tuberculosis, and Mycobacterium
leprae.26 Using experimental animals, Deem et al27 found
that T-cell lymphocytes could directly kill N asteroides
when obtained from previously immunized animals. This
effect was antigen specific because unrelated microorgan-
isms were not affected and direct contact between
N asteroides cells and T lymphocytes was necessary to
produce bacterial destruction.
T cell–mediated immune response to eumycetoma
fungi has been studied in humans by Mahgoub and
coworkers.28 They claimed that patients with eumycetoma
presented a weak cell-mediated response determined by
skin reaction to dinitrochlorobenzene. They also reported
that lymphocyte proliferative response to phytohemagglu-
tinin was also decreased in those patients. No evidence,
however, was provided to differentiate between a primary
immune deficiency and a secondary effect because of
severe infection.
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199
In the case of actinomycetoma, González-Ochoa and
Baranda29 found that patients with severe lesions accompa-
nied by extensive tissue destruction presented a weak skin
reaction to a N brasiliensis polysaccharide. Whether this
represented a Th-1 or Th-2 response was not determined.
Role of B lymphocytes and antibodies in host
resistance to mycetoma
Several studies in experimental mice infected with
M tuberculosis, L monocytogenes, or N asteroides 26 had
suggested that humoral immunity was not important in host
protection. A recent assay using immune-competent BALB/
c mice demonstrated, however, that anti–N brasiliensis
antibodies induced by purified protein antigens prevent the
development of experimental infection with N brasiliensis.
Active immunization with 3 different soluble antigens
conferred complete protection, although the protective effect
was transitory and had no memory.
Transference of purified antigen-specific anti–N brasi-
liensis IgM antibodies to naive mice, after infection with
this microorganism, produced a remarkable microbiocidal
effect. In contrast, hyperimmune sera containing a high IgG
anti–N brasiliensis antibody titer did not produced a
protective effect.30 This unexpected finding may explain
the 5-month delay needed for the development of myce-
toma lesions after N brasiliensis infection of F1 CBA/N 
DBA2 hybrid male mice. These animals have an antibody
defect manifested by the inability to produce IgG antibody
isotype but retain the ability to produce IgM antibodies.
The IgM anti–N brasiliensis antibodies decrease the initial
bacterial load, but after lowering the IgM titer, the
remaining bacilli multiply again, producing the mycetoma
lesions. Using N asteroides, Beaman and coworkers31
found that the F1 defective males were no more susceptible
than the female’s littermates (that had an intact immune
system), although they do not produce IgG antibodies.
Early IgM antinocardial antibodies, however, have been
shown to be effective in controlling N brasiliensis in
experimental infection.
Immune response in the diagnosis and prognosis
of mycetoma
Cellular and humoral immune responses have been
widely used in the diagnosis of bacterial and fungal
infections. To date, however, there are no specific and
reliable serologic or immunologic tests useful in the
diagnosis of mycetoma. This is in part because of the lack
of specific antigens that do not cross-react with antibodies
of infections caused by other related microorganisms. In the
case of nocardial infections, there have been several
developments. Angeles and Sugar32,33 described the use
of a 55-kDa protein for the diagnosis of pulmonary
nocardiosis caused by N asteroides. There was cross-
reaction, however, with Nocardia otitidiscaviarum and
N brasiliensis species. This test has been used clinically
200
in the serodiagnosis of nocardiosis. In the case of N
brasiliensis mycetoma, an enzyme-linked immunosorbent
assay test has been developed by Salinas-Carmona et al17
using P24, the 24-kDa immunodominant antigen of this
bacterium. This test has been used to determine antibody
titers in untreated, undertreated, and cured patients with
actinomycetoma. Active infection was associated with a
high antibody titer. Furthermore, the response to treatment
showed good correlation between clinical improvement and
decline in antibody titer.
Attempts have been made to develop a delayed-type
hypersensitivity test in mycetoma using microbial antigens,
but in most cases the assays have not been sensitive enough,
or represented, as in the case of aerobic actinomycetic
infection, cross-reactions with tuberculosis, and leprosy.34,35
The study and selection of specific antigens inducing
delayed-type hypersensitivity deserve future studies.
Differential diagnosis
Several diseases such as tuberculosis, osteomyelitis,
coccidioidomycosis, phaeohyphomycosis, sporotrichosis,
and other fungal infections, as well as actinomycosis,
botryomycosis, and tumors of the bone and soft tissues
must be considered in the differential diagnosis of myceto-
ma. Some of these infections are restricted to specific
epidemiologic areas and this could help the clinician to
include them or not in the differential diagnosis.
Treatment
The antimicrobial treatment of actinomycetoma began in
1941 when sulfanilamide and sulfadiazine were the first
antimicrobial agents used successfully in the treatment of
actinomycetoma.36 Later that same decade, 4,4V-diaminodi-
phenylsulfone was also shown to be effective. Later, other
Table 3 Drugs useful for the treatment of aerobic actinomycete
infections
Aminoglycosides Amikacin
Netilmicin
Beta-lactamic Amoxicillin-clavulanic acid
Carbapenem Imipenem
Oxazolidinones Linezolid
DA-7867a
Quinolones Ciprofloxacin
Gatifloxacina
Moxifloxacina
Garenoxacina
Sulfonamides 4,4V-Diaminodiphenylsulfone
SXT
Tetracyclines Oxytetracycline
Minocycline
a bials, and, therefore, it is necessary to evaluate other
In vitro susceptibility data only; not yet clinically tested.
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O. Welsh et al.
drugs such as isoniazid, streptomycin, rifampicin, and
minocycline were also used with variable cure rate. By the
end of the 1960s, treatment with trimethoprim-sulfamethox-
azole (SXT) had become the gold standard for the treatment
of this disease (Table 3). SXT exerts its antibacterial action
by synergistically interfering in the folate metabolic
pathway of the susceptible actinomycetes.36
Trimethoprim-sulfamethoxazole is given at a dosage of
8/40 mg/kg per day. A cure rate of around 60% can be
achieved, although long-term treatment is often necessary.
The main adverse reactions are gastrointestinal symptoms,
rash that may be fulminant as in the Stevens-Johnson
syndrome, and hematologic side effects such as anemia
and leucopenia. Mahgoub37 evaluated several combina-
tions and the best results were obtained when combining
SXT plus streptomycin.
Patients with actinomycetoma unresponsive to treat-
ment with SXT require the administration of other
antimicrobials such as amoxicillin-clavulanic acid 1.5 g
daily for up to 6 months.38
In our department, we have used amikacin in combina-
tion with SXT in the treatment of actinomycetoma cases not
cured with SXT alone or with extensive lesions including
bone or other organ involvement.39 Amikacin is a bacteri-
cidal aminoglycoside with a broad antibacterial spectrum
that inhibits bacterial protein synthesis by interfering with
the 30S ribosomal subunit. In vitro assays have demon-
strated a high inhibitory activity of amikacin against most
Nocardia species with the exception of N transvalensis.40,41
As with other aminoglycosides, amikacin has potential for
renal and ototoxicity.
Amikacin-SXT can be given in cycles lasting 5 weeks.
The dosage of amikacin is 15 mg/kg per day IM or IV for 3
weeks and SXT 8/40 mg/kg per day is given orally for 5
weeks. During the last 2 weeks of each cycle, audiometry
and creatinine clearance should be performed.39 Up to 4
cycles may be administered depending on the persistence of
lesions, positive microbial isolation from lesions, or the
appearance of side effects. Treatment must be administered
continuously to minimize the development of secondary
resistance to amikacin.
Where the actinomycete is resistant to amikacin, netil-
micin may offer an alternative treatment. For an adult, a
total daily dose of 300 mg daily, in combination with SXT
as above, is given.
Recently, a high sensitivity of N brasiliensis strains to
linezolid has been reported.42 An actinomycetoma murine
model of infection showed the inhibition of the development
of mycetoma lesions in animals treated with linezolid.43
This drug has been proven to be effective in subcutaneous
nocardosis with a good therapeutic result.44 Owing to its
high cost, this drug is used only for cases unresponsive to
other treatments.
Infecting bacteria can become resistant to antimicro-
drugs, both in vitro and in vivo. Moxifloxacin, gatifloxacin,
Mycetoma
garenoxacin, and an experimental oxazolidinone, DA-
7867, have shown in vitro activity against N brasiliensis
and A madurae. 45,46 In vivo assays, using experimental
models of infection with actinomycetes, as well as the
treatment of human cases of nocardiosis resistant to
standard therapy, are necessary to evaluate the therapeutic
value of these drugs.
Eumycetoma
In contrast with the successful treatment obtained
with antimicrobials in actinomycetoma, the treatment of
eumycetoma (caused by true fungi) remains a therapeu-
tic challenge. More than 50% of eumycetoma cases
treated with imidazoles and triazoles respond well to
treatment, particularly in those cases where the infection
is limited to the subcutaneous tissue and the patient is
otherwise immunocompetent. Ketoconazole (400 mg/d),
itraconazole (300-400 mg/d), and amphotericin B
(0.5-1.25 mg/kg per day) have been reported to be
effective in some patients.
Treatment of eumycetoma with other triazoles, such as
posaconazole and voriconazole, have been successful in
systemic infections caused by S apiospermum. 47,48 Terbi-
nafine at a dose of 500 to 1000 mg/d has been used in the
treatment of eumycetomas, producing a cure in about 50%
of cases.49-51
Surgical therapy in eumycetomas is useful if lesions are
limited. Surgery should be preceded and followed by
systemic antimycotic treatment as described above. Surgery
may also be indicated in limited lesions in which there is
bone involvement or where antifungal therapy alone has not
been successful. Medical treatment should be given for 2 to
4 or more years. The development of side effects may limit
the use of some agents. The cost of the medical treatment for
such a length of time and the adherence of the patient with
the treatment are other factors that may mitigate against
successful treatment. In vitro susceptibility studies have
been shown to be of some value in selecting the most
effective antifungal drug.52
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