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Chromoblastomycosis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Chromoblastomycosis is a chronic fungal infection of cutaneous and subcutaneous tissues prevalent in tropical and subtropical climates including Central and South America, Africa, Asia (highest incidence in Japan), and Oceania (first described in Australia), with cases also reported from New Zealand and Solomon Islands. Most cases reported outside the tropical areas, particularly in Europe, are considered imported dermatoses. It is caused by the traumatic cutaneous implantation of dimorphic pigmented (dematiaceous) fungi, classified in the order Chaetothyriales. These produce characteristic thick-walled sclerotic bodies (also known as muriform fumagoid or Medlar bodies ) in infected tissues. The most common etiologic agents are Fonsecaea pedrosoi, Phialophora verrucosa and Cladophialophora carrionii . Clinically, chromoblastomycosis presents as plaques, nodules, tumors, cicatricial or verrucous exophytic lesions, which are commonly located on the feet and lower legs. Lesions are indolent and slow growing; over years they extend centrifugally, leaving central areas of scarring. Disease is commonly localized but can spread through autoinoculation or lymphatic dissemination, producing metastatic lesions away from the primary site. Complications include ulceration, secondary bacterial infection, and lymphedema., Rarely, malignant transformation (squamous cell carcinoma) in chronic lesions and systemic involvement have been reported.
Management Strategy
Chromoblastomycosis is a difficult-to-treat mycosis characterized by low cure and high rates of relapse, particularly in chronic and extensive disease. There are no clinical trials that determine the best therapeutic approach. Studies report highly variable rates of clinical and mycological cure, ranging from 15% to 80%. The choice of treatment and outcome depend on the etiologic agent, severity and extent of the lesions, clinical topography, and the presence of complications (dermal fibrosis and edema may reduce tissue antifungal drug levels). F. pedrosoi is the most common etiologic agent but has the lowest sensitivity to the major systemic antifungal agents. C. carrionii and P. verrucosa are much more sensitive and have been found to respond more favorably to treatment.
Surgical excision may be successful for small and localized lesions. It is performed with wide surgical margins and is usually accompanied by chemotherapy in order to reduce the risk of recurrence. Curettage and electrodessication is not recommended because it may promote lymphatic spread. Other physical modalities include cryotherapy with liquid nitrogen, as well as thermotherapy (applying local heat to produce controlled temperatures ranging from 42°C to 45°C, which inhibit fungal growth) using a variety of methods, including benzene pocket warmers and pocket-handkerchief–type warmers. Cryosurgery and thermotherapy have the advantage that they are relatively inexpensive treatment options.
There are no comparative trials of antifungal chemotherapy for chromoblastomycosis. Itraconazole (100–400 mg daily) and terbinafine (250–500 mg daily) are considered first-line treatments, with both drugs having shown high in vitro activity against the causative agents of chromoblastomycosis. They are typically given for long periods at high doses. Dual therapy with itraconazole and terbinafine is recommended if it is affordable and tolerated. It is not uncommon for more than one treatment modality to be used, such as oral antifungals combined with surgery, cryotherapy, or thermotherapy. For example, itraconazole and/or terbinafine combined with cryosurgery is advocated for extensive disease. The antifungal is given first until there is a maximum reduction in lesion size, which usually requires 6–12 months of chemotherapy. The lesions then require several treatments with cryosurgery.
Of the other antifungal agents, ketoconazole is not recommended due to toxicity at high doses. Despite a few cases in the early literature reporting success with fluconazole, it too is not recommended as in vitro studies have shown that it has little activity against black fungi. Flucytosine (converted into 5-fluorouracil in fungal cells) was an early treatment that demonstrated some degree of efficacy. It is associated with a high risk of developing resistance, but this can be overcome if it is used in combination with another antifungal. It is also hepatotoxic and myelotoxic, requiring regular monitoring of serum levels. It is rarely used now except for resistant cases. Amphotericin B (AmB) monotherapy is ineffective, and even in combination with other antifungals, results are generally poor. However, AmB and flucytosine dual therapy has demonstrated efficacy, with in vitro studies having demonstrated synergistic activity between the two drugs. The new second-generation azoles, such as posaconazole and voriconazole, have shown acceptable results in case reports, but experience to date is limited mainly due to high costs in endemic areas.
Other modalities of treatment, including imiquimod, conventional photodynamic therapy, and carbon dioxide laser photocoagulation, are mainly anecdotal.
A positive direct examination of scrapings in 10% potassium hydroxide will demonstrate thick-walled, brown sclerotic cells that are pathognomonic of chromoblastomycosis, irrespective of the causative species. Specimens are more likely to yield a positive result if they include the ‘black dots’ visible on the surface of the lesion. Culture enables the identification of the causative agent. It is a slow-growing fungus and culture may be inconclusive due to poor morphologic differentiation. Polymerase chain reaction (PCR) has been developed for the identification of Fonsecaea and C. carrionii. Serologic tests such as enzyme-linked immunosorbent assay (ELISA) can be useful in evaluating therapy response, but like PCR they are not widely available in most endemic settings. A biopsy demonstrates the typical sclerotic bodies in a granulomatous lesion that may be accompanied by transepithelial elimination.
Treating chromoblastomycosis with systemic antifungals
Bonifaz A, Paredes-Solis V, Saul A. Expert Opin Pharmacother 2004; 5: 247–54.
A review article highlighting the difficulties in treating this condition. The authors state that the best results for therapy have been obtained with the combination and use of high-dose itraconazole and terbinafine for a minimum treatment period of 6–12 months.
Chromoblastomycosis
Lopez-Martinez R, Mendez Tovar LJ. Clin Dermatol 2007; 25: 188–94.
A comprehensive review article. Itraconazole is considered the treatment of choice in combination with surgery in some cases.
Chromoblastomycosis: an overview of clinical manifestations diagnosis and treatment
Queiroz-Telles F, Esterre P, Perez-Blanco M, et al. Med Mycol 2009; 47: 3–15.
The authors state that there is no treatment of choice but rather several treatment options: they suggest that physical therapies should enhance chemotherapy and that systemic combination therapies may increase cure rate but may be associated with a higher risk of adverse effects.
Pulse itraconazole 400 mg daily in the treatment of chromoblastomycosis
Ungpakorn R, Reangchainam S. Clin Exp Dermatol 2006; 31: 245–7.
In this small study, six cases of F. pedrosoi infection in Thailand were treated with pulse itraconazole 400 mg daily, for one week each month. All achieved clinical and mycological cure. Four patients were cured after 12 pulses of treatment, and one after 15 pulses of treatment. The remaining patient required 20 pulses of itraconazole as well as cryosurgery. Disease severity and duration did not appear to be predictive of treatment response. This study demonstrated that the monthly pulse regimen is well tolerated and as effective as the conventional continuous 200–400 mg daily regimen for the treatment of F. pedrosoi. The authors recommend that treatment is continued until absence of organisms is proven by histology and tissue culture. Given that the total drug dosage is reduced, there is a marked reduction in cost of therapy by 50% to 75%. They also claim that pulse therapy is associated with higher compliance, although therapy duration remains long.
The cost of long-term itraconazole therapy is expensive in endemic settings, making this an important and relevant study.
Treatment of chromoblastomycosis with itraconazole, cryosurgery and a combination of both
Bonifaz A, Martinez-Soto E, Carrasco-Gerard E, et al. Int J Dermatol 1997; 36: 542–7.
This study included 12 patients assigned to three different groups. Group 1, with small lesions, was treated with itraconazole 300 mg/day. Group 2, also with small lesions, was treated with one or more sessions of cryosurgery. Group 3, with large lesions, started treatment with itraconazole 300 mg/day until reduction of lesions was achieved, followed by one or more sessions of cryosurgery. The results showed complete clinical and mycologic cure in two out of four patients in both groups 1 and 3. All four patients in group 2 achieved complete cure.
Although the case numbers were small, this study suggests that cryosurgery is a more suitable treatment option than antifungal therapy for small lesions.
Treatment of chromomycosis with terbinafine: preliminary reports of an open pilot study
Esterre P, Inzan CK, Ramarcel ER, et al. Br J Dermatol 1996; 134: 33–6.
A multicentre study from Madagascar. Of 43 patients treated, 36 ( F. pedrosoi , n = 29; C. carrionii , n = 7) could be completely evaluated. Approximately one-third of the patients had been resistant to previous treatment with thiabendazole. Oral terbinafine 500 mg daily was given for 6–12 months. Within 2–4 months of commencement of treatment, there was a marked clinical improvement with resolution of secondary bacterial infection, edema, and elephantiasis. There was mycologic cure in 83% (24/29) of patients infected with F. pedrosoi at 12 months. Of those infected with C. carrionii, there was a cure in one and clinical improvement in a further three. Total cure was observed even in imidazole-refractory patients or those with chronic disease present for over 10 years. There was a mild transient rise in hepatic enzymes in some patients, but no serious adverse effects were reported.
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