Treatment of chromoblastomycosis
Lucia Tuffanelli, MD, and Peter B. Milburn, MD Brooklyn, New York
Treatment of chromoblastomycosis is frequently difficult and unsatisfactory. A representa-
tive case is presented of this chronic subcutaneous fungal infection, characterized by warty,
cauliflower-like lesions usually on the extremities. Chromoblastomycosis and its treatment are
reviewed, with attention to itraconazole, a new triazole compound, as the possible drug of
choice. (J AM ACAD DERMATOL 1990;23:728-32.)
Chromoblastomycosis is a slowly progressive and
frequently debilitating subcutaneous fungal infec-
tion caused by a group of dematiaceous fungi. The
main organisms are Fonsecaea pedrosoi, Clado-
sporium carrionii, F. compacta, Phialophora ver-
rucosa, and Rhinocladiella aquaspersa. In tissue
and exudate, these species produce dark brown sep-
tate cells that occur in pairs and small clusters. These
sclerotic bodies, or Medlar bodies, make these spe-
cies the distinctive organisms in chromoblastomy-
coSiS.I-5
Chromoblastomycosis occurs primarily in tropi-
cal and subtropical regions in men between 30 and
50 years of age. The etiologic agents are traumati-
cally introduced into tissue, usually through occu-
pational exposure.v" The lesions of chromoblasto-
mycosis are generally on the lower extremities. They
begin as small erythematous papules that gradually
enlarge to display varying morphologies'': verrucous
or velvety nodules," cauliflower-like tumors, and
psoriasiform plaques. Scarring is common where
healing has occurred. Lesions may spread contigu-
ouslyor as satellite lesions along lymphatics. 4 Rarely,
it is spread hematogenously but cases of central ner-
vous system lesions have been reported. 8 , 9 The dis-
ease does not invade underlying muscle or bone.
Late complications include ulceration and second-
ary infection, extensive fibrosis, pain, decreased
modality, and lymphatic blockage causing lymphe-
dema and elephantiasls.v'" Squamous cell carci-
noma has arisen in lesions of chromoblastomy-
COSiS. 11
From the Department of Dermatology, State University of New York,
Health Science Center at Brooklyn.
Reprint requests: Peter B. Milburn, MD, Department of Dermatology,
Box 46, State University of New York, Health Science Center,
Brooklyn, NY 11203.
16/1/17817
728
Chromoblastomycosis is notoriously difficult to
treat. We report the case of a patient with this infec-
tion and discuss treatment. Itraconazole is suggested
as the drug of choice.
CASE REPORT
A 50-year-old man from the Dominican Republic had
verrucous nodules and plaques on the left leg of 9 years'
duration. His medical problems included hypertension
and adult-onset diabetes mellitus, treated with enalopril,
2.5 rug/day, and regular insulin, 40 U /day.
The patient came to New York in 1969, where he
worked in a welding factory and a naval ship yard. He
denies any trauma to the left leg. In 1977, subcutaneous
nodules developed that progressed into extensive verru-
cous lesionscovering the entire left foot and lowerleg (Fig.
1). A biopsy specimen in 1981 showed pseudoepitheliom-
atous epidermal hyperplasia, an intraepidermal abscess,
and a granulomatous dermal infiltrate with fibrosis (Fig.
2). High-power magnification revealed necrosis within
the granuloma that contains fungal spores (Medlar
bodies)? in clusters in the dermis. A fungal culture grew
F. pedrosoi, thereby confirming the diagnosis of chromo-
blastomycosis. The patient was initially treated with ke-
toconazole, 200 mg/day, When the disease progressed,
ketoconazole was increased to 400 mg/day, and 5-
fluorocytosine (flucytosine), 1500 mg four times a day,
was added. This combination arrested the appearance of
new lesions and reduced the size of existing ones. The pa-
tient's response to this therapy was reported in 1983. 12
Improvement continued until 1985, when the patient dis-
continued medications for 6 months. New lesions ap-
peared, and he was treated again with ketoconazole and
flucytosine for 8 months. Despite this therapy, the disease
progressed (Fig. 3), and lesionsappeared for the first time
on the thigh.
In 1986, treatment with itraconazole was begun,
initially at 100 mg/day. One month later, treatment was
stopped briefly because values from liver function tests
were elevated. Evaluation indicated that a reaction to
chlorpropamide was the most likely cause, and results of
Volume 23
Number 4, Part 1
October 1990 Chromoblastomycosis 729

Fig. 1. Extent of chromoblastomycosis in 1981.

liver function tests returned to normal values after chlor-

propamide was stopped. Itraconazole was started again
without further problems.
The dosage of itraconazole was increased to 400 mg/
day during a period of several months. In the first months
oftreatment, no improvement was seen. To evaluate this
lack of response, several investigations were done. An in-
traepidermal skin test for tuberculosis was negative,
although a test for mumps antigen was positive. Repeat
fungal cultures again revealed F. pedrosoi. Minimum in-
hibitory concentrations testing on cultures taken from this
patient in 1981 and 1987 indicated high sensitivity of the
organism to itraconazole. The serum itraconazole level
after a morning dose of 200 rng was 4.9 J,Lg/ml, well within
the therapeutic range (1 to 10 J,Lg/ml) (Dr. David Rinal-
di, personal communication, June 1987.)
Treatment with itraconazole at 400 mg/day was con-
tinued. Improvement was noted several months later, and
since then the lesions have substantially resolved, leaving
considerable scarring (Fig. 4). In addition, intermittent
selective excision and cryotherapy of persisting isolated
lesions have been performed. No new lesions had ap-
peared a year after treatment. The patient has reported
occasional bloating with mild abdominal pain. Results of
liver function tests and other laboratory examinations Fig. 2. Scanning power photomicrograph shows pseu-
have been normal, with the exception of poorly controlled doepitheliomatous epidermal hyperplasia, large intraepi-
diabetes mellitus. dermal abscess, and granulomatous infiltrate. (X20.)

DISCUSSION
Treatment of chromoblastomycosis has been
problematic. As with our patient, numerous ap-
proaches have been used, including surgery, physi-
cal agents, and chemotherapy. Small lesions of
chromoblastomycosis can be removed with wide and
deep excision. Although curettage and desiccation,
and recently Mohs surgery,':' have been used, these
therapies are discouraged because recurrence is
common, and early lymphatic spread can occur.v 10
Successful treatment of chromoblastomycosis with
the carbon dioxide laser in patients with limited dis-
ease has been reported.!? Both cryotherapyv'<!?
and topical heat therapylS-20 have been reported
useful as well.
Systemic medications are the most common
method of treatment for widespread disease (Table

730 Tuffanelli and Milburn
Fig. 3. New hyperkeratotic nodules appearing at the edge of previously healed lesions in
1987.
Fig. 4. Appearance of ankle after treatment with itra-
conazole for 1 year.
I). Numerous agents have been used alone and in
combination. Intralesional and parenteral ampho-
tericin B has had minimal success. Side effects are
common and significant. Used alone, amphotericin
B is currently considered ineffective therapy for
chromoblastomycosis.U'<' Thiabendazole, an anti-
helminthic, has cure rates between 25% and 50% (on
Journal of the
American Academy of
Dermatology
the basis of short-term follow-up) when used for
chromoblastomycosis. However, up to 25% of those
treated developed a non-dose-related hepatotoxic
hypersensitivity reaction. 10, 24
Flucytosine, an inhibitor of nucleic acid synthe-
sis in fungi, is effective in chromoblastomyco-
sis.21, 22,25-31 In the largest series, Lopes et a1. 29
treated 23 patients in 6 years and achieved a 41%
cure rate. Adverse reactions are few, rare, and usu-
ally reversible. Resistance to ftucytosine can occur
quickly, especially in patients with widespread le-
sions. This resistance cannot be overcome by in-
creasing the dose or adding other antifungal agents.
This may have been a factor in our patient's therapy.
Ketoconazole32,33 has been used successfully in
many fungal diseases. Cuce et a1.,33 however, con-
cluded that therapy with ketoconazole was only
moderately effective for chromoblastomycosis, and
results were not superior to those obtained with
flucytosine alone or in combination with amphoteri-
cin B. The incidence of side effects of ketoconazole
is actually low but they may be significant. 2 1, 22, 32-35
Itraconazole is the newest systemic antifungal
agent effective in the treatment of chromo-
blastomycosis.P"? Like ketoconazolc, itraconazole
has broad-spectrum coverage"!,42and is effective in
treating several deep fungal infections43.45 and su-
perficial mycoses.46-49 ltraconazole acts by specifi-
cally interfering with fungal synthetic pathways; it
interferes with cytochrome P-450 enzymes, causes
accumulation of lanosterol-like 14-methyl sterols,
and affects oxidative and peroxidative enzymes
causing increased cellular hydrogen peroxide,
thereby contributing to disruption of the fungal
plasma membrane and the fungal cell wall."! It is
Volume 23
Number 4, Part 1
October 1990
Table I. Chemotherapeutic modalities in chromoblastomycosis
Duration
___I Drug Dose of therapy
Thiabendazole 25 mg/kgjday (t.i.d.) 3-8 mo
Flucytosine 150 mg/kgjday (q.i.d.) >6mo
Ketoconazole 200-400 mg/day (b.i.d.) >6mo
Itraconazole 200-400 mg/day (bj.d.) >6mo
C/. Gastrointestinal.
essentially devoid of potential to induce cytochrome
P-450 in mammalian cells.50
Highest peak plasma concentrations of itracona-
zole are reached when it is taken with meals. Steady
plasma concentration is reached after 4 days of 200
mg/day, taken orally" Itraconazole has high af-
finity for the epidermis and has been detected in se-
bum for up to 4 weeks after treatment cessation.52
Use of itraconazole in chromoblastomycosis has
been reported in 29 patients. 36-40 Nine patients with
C. carrionii infection had apparent cures. 36 Infec-
tions with F. pedrosoi respond more slowly to treat-
ment, but significant improvement occurred in all
patients treated. 36 , 38, 40 The dose recommended is
200 to 400 rug/day for a prolonged period, usually
between 6 and 12 months, but frequently longer.
Host factors, such as poorly controlled diabetes
mellitus, can delay response to treatment.F Our pa-
tient's slow response to therapy may have been due
in part to poorly controlled diabetes.
Adverse reactions are seen in approximately 2.8%
of all patients who have used itraconazole." Those
most frequently reported are nausea, epigastric pain,
headache, vomiting, dizziness, fatigue, abdominal
cramps, urticaria, and pruritus. One case of signif-
icant hepatic toxicity has been reported to the man-
ufacturer (Janssen Pharmaceuticals) (personal com-
munication, November 1988). Liver function should
be monitored. Itraconazole has been shown to be
teratogenic in rats and is contraindicated in women
of childbearing age. 53 It does not affect levels of
plasma testosterone, aldosterone, follicle-stimulat-
ing hormone, luteinizing hormone, or cholesterol in
animals or human volunteer subjects. 52,54
Chromoblastomycosis 731
Response
- -- - - - - - -
(%) Toxicity
25-50 Nausea and vomiting
Non-dose-dependent hepatotoxicity
40 GI discomfort (mild)
Hepatotoxicity (elevated
transaminases)
41 Hepatotoxicity
Decreases testosterone and
cortisol
Teratogenic
80-90 GI discomfort
Headache
Teratogenic
Although experience with itraconazole in the
treatment of patients with chromoblastomycosis is
limited, this drug has shown excellent results. Some
patients may require prolonged therapy and can
have prolonged remission, if not total cure. Given the
low incidence of side effects compared with other
available treatments, itraconazole should be consid-
ered early in the treatment of chromoblastomycosis.
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