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Asian Journal of Healthy and Science
p-ISSN: 2980-4302
e-ISSN: 2980-4310
Vol. 3 No. 12 December, 2024
Treatment of Severe Chromoblastomycosis Non Responsive with
Itraconazole : A Case Report
Indah Wardani1*, Muhammad Wahyu Riyanto2
Rumah Sakit Umum Daerah dr. Soeroto Ngawi, Indonesia
Emails: indahwardani96@gmail.com
Abstract
Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues
caused by pigmented (dematiaceous) fungi. Itraconazole is widely used as a first-line
antifungal therapy due to its availability and effectiveness. However, in certain cases,
patients may not respond to itraconazole, necessitating alternative treatments. This
research aimed to analyze the clinical response to alternative antifungal therapy in a
case of chromoblastomycosis unresponsive to itraconazole. This case report involves a
52-year-old male patient presenting with progressively growing, itchy, blackened
lesions on the plantar surface extending to the left ankle for 10 years. The condition was
preceded by a history of untreated clavus and thorn trauma from sharp twigs or grass.
Periodic Acid-Schiff (PAS) staining confirmed the presence of Medlar bodies,
establishing the diagnosis of chromoblastomycosis. The patient received itraconazole
200 mg twice daily for 6 months without clinical improvement. Treatment was
subsequently switched to fluconazole 150 mg once daily for 4 months, resulting in
significant clinical improvement. This case demonstrates that while itraconazole is the
standard treatment for chromoblastomycosis, alternative antifungal agents such as
fluconazole can be effective in cases of itraconazole resistance or non-responsiveness.
The findings emphasize the importance of tailored therapy based on clinical response
and suggest that fluconazole may be considered as a viable alternative in such cases.
Keywords: Chromoblastomycosis, Case Report, Itraconazole, Fluconazole.
INTRODUCTION
Chromoblastomycosis is a chronic and progressive fungal infection of the skin and
subcutaneous tissues, caused by pigmented (dematiaceous) fungi that are introduced
into the dermis through minor trauma (Damayanti et al., 2022). This condition is
particularly challenging to manage due to its chronicity, potential for severe
complications, and resistance to conventional antifungal therapies. Globally,
chromoblastomycosis is considered a neglected tropical disease, predominantly affecting
individuals in tropical and subtropical regions. The disease’s etiological agents, such as
Cladophialophora carrionii
and
Fonsecaea pedrosoi
, are saprophytic fungi commonly
found in soil, decaying wood, and plant debris (Queiroz-Telles et al., 2017); (Queiroz-
Telles & Santos, 2023).
While
C. carrionii
is more prevalent in arid climates and
F. pedrosoi
is predominant
in humid forests, both fungi share the characteristic of infecting individuals through
minor trauma, such as cuts or abrasions, often sustained during agricultural or gardening
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361
activities. The infection typically manifests as asymptomatic, erythematous nodules that
gradually develop into well-defined, verrucous, and scaly plaques over a period of months
to years (Arguello-Guerra et al., 2016). These lesions are often localized to the lower
limbs, correlating with the site of initial trauma. Despite being a chronic and localized
disease, chromoblastomycosis can significantly impair quality of life, especially in
advanced cases.
Effective management of chromoblastomycosis remains a global challenge due to
the disease's chronic nature and resistance to standard therapies (Chowdhary et al.,
2014). Current treatment modalities include antifungal agents, such as itraconazole and
terbinafine, either alone or in combination. However, treatment outcomes are often
suboptimal in moderate to severe cases. According to (Sanap et al., 2022), treatment
success is hampered by factors such as delayed diagnosis, the presence of extensive
lesions, and patient non-compliance. Furthermore, antifungal resistance, particularly to
itraconazole—the most commonly prescribed first-line therapy—has been increasingly
reported, necessitating the exploration of alternative therapeutic options (Logan et al.,
2022).
In clinical practice, second-line therapies such as fluconazole have been evaluated,
albeit rarely, in the context of chromoblastomycosis. Fluconazole, a triazole antifungal
agent, is characterized by its excellent oral bioavailability, low protein-binding, and high
tissue penetration. Despite its widespread use in other systemic fungal infections, the
efficacy of fluconazole in treating chromoblastomycosis remains poorly documented,
with only a handful of case reports highlighting its potential utility. This gap in knowledge
underscores the urgency of systematically evaluating fluconazole as a viable alternative,
particularly for patients who do not respond to itraconazole.
Several studies have highlighted the challenges and potential strategies in
managing chromoblastomycosis. For instance, (Brandt & Warnock, 2023) reviewed the
clinical presentations and therapeutic outcomes of patients with chromoblastomycosis,
emphasizing the variability in response to itraconazole and terbinafine. Their findings
suggested that combination therapies or adjunctive surgical interventions might be
necessary for refractory cases. Similarly, a research by (Smith et al., 2024) discussed the
global epidemiology and treatment approaches for chromoblastomycosis, advocating for
the development of novel antifungal agents and personalized treatment regimens.
Case reports have also provided valuable insights into the potential use of
fluconazole. One report documented a patient with moderate chromoblastomycosis who
demonstrated significant clinical improvement following fluconazole therapy, despite
initial resistance to itraconazole. These findings suggest that fluconazole may offer a
promising alternative for managing refractory cases, warranting further investigation.
Case Illustration
A 52-years-old man from rural area came to the dermatovenereology polyclinic dr.
Soeroto hospital with the main complaint of progressively growing, itchy, and blackened
plantar to left ankle since 10 years ago. It started with clavus without adequate treatment
then progressively widened. He complained painful (VAS 7/10) and itchy on his left foot.
Previously, the patient likes gardening in the yard. The patient had a garden at home and
when gardening he did not wear sandals. The patient was often scratched by sharp twigs
or grass when gardening but never had serious injuries. Physical examination showed
multiple verucous nodules and papules on the surface of hyperpigmented macules bases
with medial diameter 41,5 cm on left plantar to dorsal pedis (Figure 1). Previously, he
had been treated with itrakonazol 2 time daily for 6 months di another hospital but there
were no clinical improvement. The patient first came dr. Soeroto Hospital in May 2024.
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Biopsy was performed and it showed atypic cells followed by histopathological
examination which showed hyperkeratosis, acanthosis, and papillomatosis of epidermis
and granulomatous reaction with mononuclear cells infiltration in brownish yellow
pigment at the dermis. Periodic Scid-Schiff (PAS) staining demonstrated Medlar bodies
and no signs of malignancy were found (Figure 2). In conclusion, histopathology
examination can support the diagnosis of chromoblastomycosis. The diagnosis was
chromoblastomycosis. The patient was treated with fluconazole 1 time daily and he was
educated to maintain foot hygiene. After 4 months follow up of treatment, the patient
showed clinical improvement with reduced lesion size with medial diameter 37,5 cm on
left plantar to dorsal pedis, reduced pain (VAS 3/10) and itchiness (Figure 3). Laboratory
results over the last 4 months treatment follow up with fluconazole did not show any
increase in urea, creatinine, SGOT, SGPT levels, and no side effects of the drug were
reported by the patient.
Figure 1. Multiple verucous nodules and papules on the surface of hyperpigmented
macules bases on left plantar to dorsal pedis
Figure 2. Periodic Scid-Schiff (PAS) staining demonstrated Medlar bodies and no signs of
malignancy were found
Figure 3. Skin lesion after 4 months treated with Fluconazole 150mg 1 time daily
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The reported case underscores the urgent need to explore alternative treatment
strategies for chromoblastomycosis, particularly in patients unresponsive to
itraconazole. The successful use of fluconazole in this case highlights its potential as a safe
and effective second-line therapy. Unlike itraconazole, which is associated with variable
absorption and significant drug-drug interactions, fluconazole offers a more predictable
pharmacokinetic profile, making it an attractive option for managing refractory cases.
The novelty of this research lies in its systematic evaluation of fluconazole as a
therapeutic alternative for chromoblastomycosis. By documenting the clinical response
and safety profile of fluconazole in a patient with itraconazole-resistant
chromoblastomycosis, this research contributes valuable data to the limited body of
literature on this topic. Additionally, it provides a foundation for future research aimed
at optimizing antifungal therapy for this challenging condition.
Based on the above background, this research aims to evaluate the clinical response
to fluconazole as an alternative treatment for chromoblastomycosis in a patient
unresponsive to itraconazole therapy, contributing to a better understanding of its
efficacy and safety as a second-line treatment. So that the benefits in this research are to
provide new insights related to the use of fluconazole as an alternative therapy in cases
of chromoblastomycosis that does not respond to itraconazole therapy, especially in
terms of its clinical effectiveness and safety profile. This research is expected to serve as
a basis for the development of clinical guidelines in managing difficult-to-treat
chromoblastomycosis, as well as assisting medical practitioners in choosing more
appropriate antifungal therapy for patients with similar conditions.
RESEARCH METHOD
This research employed a case report design to examine the clinical management
and treatment outcomes of a 52-year-old male patient diagnosed with
chromoblastomycosis, unresponsive to standard itraconazole therapy. The subject was
selected based on the inclusion criteria of being diagnosed with chromoblastomycosis
and exhibiting resistance to itraconazole. Data collection involved clinical observations
of lesion size, pain levels (using the Visual Analog Scale), and itching, along with
histopathological examination using Periodic Acid-Schiff (PAS) staining to confirm the
presence of Medlar bodies. Regular follow-up visits monitored the patient’s clinical
response to fluconazole therapy and any potential side effects, supported by laboratory
tests measuring biochemical parameters such as urea, creatinine, SGOT, and SGPT levels
to ensure safety. Data analysis consisted of descriptive assessments of clinical
observations and laboratory results, comparative evaluation of outcomes with
fluconazole versus prior itraconazole therapy, and interpretation of findings in the
context of existing literature to highlight the potential of fluconazole as an alternative
treatment for chromoblastomycosis.
RESULTS AND DISCUSSION
Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous
tissues caused by pigmented (dematiaceous) fungi that are implanted into the dermis
from the environment (Queiroz-Telles et al., 2017). The disease affects mostly laborers
(farmers, wood cutters, latex gatherers) between 35 and 50 years of age in rural areas,
and the infection is much more common in men. The lesions are usually on the lower
limbs. Going barefoot or wearing sandals enhances the susceptibility, because the fungi
enter hands or feet after local minor trauma. There is no ethnic predominance as all races
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seem to be susceptible. This demographic epidemiology correlates with our case where
the patient are male in rural areas and he had history walking barefoot.
The human chronic infection begins with one or more nodules at the traumatized
area. Many patients do not recall an injury. Chromoblastomycosis begins as small,
asymptomatic erythematous nodules, with a slow growth over months to years (Yuliarto
et al., 2023). The lesions gradually grow to form an erythematous plaque with a well-
defined border, which subsequently expands to form irregular verrucous or
papillomatous lesions that are isolated or coalescent, often with superimposed
ulceration. Multiple lesions may occur following lymphatic and perhaps hematogenous
dissemination. The infection shows a greatly varied morphology of the lesions, among
them keloid-like, cauliflower, pedunculated, ulcerated, and cicatricial, by expanding
centrifugally. Chromoblastomycosis was classified by Carrión in 1950 into 5 type lesions
: nodular, verrucous or warty, plaque (infiltrative or erythematous), tumoral, and
cicatrical or atrophic. Complications of chromoblastomycosis are lymphadenopathy
which is due to secondary bacterial infections and, in advanced disease, lymphostasis
may resemble elephantiasis (Singh et al., 2024). Lesions are mostly seen on the lower
extremities (feet, knee, legs), followed by those located on the upper extremities (hands,
wrist, forearms). Other sites of lesions may include face, neck, dorsum, buttocks, and
rarely, on mucous membranes. Some patients complain of pruritus and pain. Despite the
protracted course of the disease, dissemination of the mycosis is rare. Occasionally,
chronic disease leads to squamous cell carcinomas.
Chromoblastomycosis is caused by a group of genetically closely related
dematiaceous fungi that have only one single-tissue form, characterized by round, thick-
walled muriform cells - sclerotic bodies (Santos et al., 2021). Five principal etiologic
agents have been recognized worldwide: Phialophora verrucosa, Fonsecaea pedrosoi,
Fonsecaea compacta, Cladosporium carrionii, and Rhinocladiella aquaspersa (Brito &
Bittencourt, 2018). Histopathology of chromoblastomycosis may show
pseudoepitheliomatous hyperplasia of the epidermis, lymphohistiocytic infiltrates, and
typical thick-walled dark-brown 'sclerotic' cells on skin biopsy confirming the presence
of a dematiaceous fungus. It is dark coloured due to melanin in the walls of the organism.
Gomori–Grocott Methenamine Silver (GMS) and PAS stains may be employed as it can
highlight the fungal forms. These sclerotic cells, also known as Medlar bodies, are globe-
shaped, cigar-colored, thick-walled structures that are 4-12 µm in diameter and these
cells are pathognemonic finding in chromoblastomycosis. In this case, histopathological
examination showed hyperkeratosis, acanthosis, and papillomatosis of epidermis and
granulomatous reaction with mononuclear cells infiltration in brownish yellow pigment
at the dermis. PAS staining examination demonstrated Medlar bodies which established
chromoblastomycosis diagnosis.
Chromoblastomycosis is a disease that is often unresponsive to many antifungal
and surgical procedures (da Silva Hellwig et al., 2019). In early localized lesions a wide
and deep excision is recommended. Efficacious treatments include physical therapies
such as cryotherapy (for lesions under 15 cm in diameter), photodynamic therapy, and
laser treatment. The main treatments for chromoblastomycosis are itraconazole 200 mg
daily, terbinafine 250 mg daily; and, in extensive cases, IV amphotericin B (up to 1 mg/kg
daily).1–3 According to several open and noncomparative clinical trials, itraconazole is
the standard therapy for chromoblastomycosis, and it is also the most commonly used
antifungal drug. Itraconazole cure rates range from 15 to 80%.6 Fluconazole is another
member of the triazole family and can be effective for chromoblastomycosis
treatment.Fluconazole is a triazole antifungal agent for the treatment of systemic fungal
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365
infections active by both oral and intravenous routes. The drug is well absorbed, its
plasma protein-binding is low (12%), and it penetrates well into tissues and body fluids.
Reports of patients with chromoblastomycosis treated with fluconazole are rare.
However, there are several case reports where fluconazole can be used effectively to treat
chromobalstomycosis.
A serious case of chromoblastomycosis was resistant to any antifungal agents and
was successfully treated with intravenous followed by oral fluconazole. Another case
reported the patient responded well to fluconazole after he was treated for 2 years and
no side effects were observed. Fluconazole therapy can cause transient mild-to-moderate
serum aminotransferase elevations and is a known cause of Drug-Induced Liver Injury
(DILI). DILI occurs within the initial few weeks of therapy. Hepatotoxicity can be
associated with hypersensitivity reactions, including eosinophilia, fever, and rash (De et
al., 2018). In this case the patient was treated with Fluconazole 1 time daily for 4 months.
After 4 months followed up, the patient showed clinical improvement with reduced pain
and size of the lesion. He also didn’t reported any side effects. Although treatable, there
are many cases refractory to treatment; therefore, early intervention with regular follow-
up is essential to reduce morbidity and mortality. Because there is rare internal organ
involvement and the disease remains mostly cutaneous, there is less likely to be mortality
due to the disease, except in certain cases, such as those with disseminated disease.
Without treatment, complications are likely to occur, and with treatment, monitoring
must be performed to observe patients for adverse effects of treatment (eg,
hepatotoxicity).
CONCLUSION
In conclusion, chromoblastomycosis is a chronic fungal infection caused by
pigmented fungi, commonly acquired through minor trauma in rural areas, as seen in the
case of a 52-year-old man who contracted the disease after repeated barefoot trauma.
Despite receiving itraconazole 200 mg twice daily for six months, the patient had no
clinical improvement in lesion size, pain, or itching. However, treatment with fluconazole
150 mg once daily for four months resulted in significant clinical improvement. This case
highlights the potential limitations of itraconazole as a standard first-line treatment for
chromoblastomycosis and underscores the need for alternative therapeutic strategies in
unresponsive cases. Successful results with fluconazole, a triazole class antifungal,
demonstrate its efficacy as a second-line treatment option for chromoblastomycosis.
This research contributes to the growing body of evidence supporting fluconazole
as a viable alternative for patients unresponsive to itraconazole. It underscores the
importance of an individualized treatment approach and provides a basis for future
research on the comparative efficacy of fluconazole in managing chromoblastomycosis.
In addition, these findings encourage clinicians to consider flexible treatment strategies
and emphasize the role of alternative antifungal agents in improving patient outcomes in
challenging cases.
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Copyright holders:
Indah Wardani, Muhammad Wahyu Riyanto (2024)
First publication right:
AJHS - Asian Journal of Healthy and Science
