Cutaneous sporotrichosis. Intermittent treatment (pulses) with itraconazole

ARTICLE

Auteur(s) : Alexandro Bonifaz, Leonel Fierro, Amado Saúl, Rosa María Ponce

Dermatology Service & Mycology Department, Hospital General de México OD, Sánchez Azcona 317 int 202, Col del Valle, 03020 Mexito City, Mexico

accepté le 6 Août 2007

Sporotrichosis is a mycosis caused by a dimorphic fungus known as Sporothrix schenckii. It usually begins with trauma-related contact with the fungus; it is endemic in some regions with a humid temperate climate. The diagnosis is usually based on the clinical features, particularly in cutaneous lymphatic cases, and is confirmed by isolation of the fungus in standard culture media [1-3].

The treatment of sporotrichosis is generally easy since the fungus is susceptible to most antifungal agents. Some authors believe that the treatment of choice is still potassium iodide (KI); however, according to others it has side effects and is not really an antifungal, but rather an immunostimulant and it is not available as a patented drug [4, 5]. Itraconazole is a triazole derivative with good in vitro activity versus S. schenckii; and according to several clinical reports it has an appropriate action [4, 6].

This is a clinical therapeutic report of the action of itraconazole administered intermittently or as pulse-therapy.

Material and methods

Once sporotrichosis was proven, patients underwent the following lab tests: complete blood count, urinalysis, and liver function tests. These tests were repeated during the treatment at monthly intervals (at each pulse) and at the end of therapy.

Once the cases of sporotrichosis were proven and the baseline laboratory data were available, all patients received oral itraconazole intermittently, i.e., 400 mg/day divided into two intakes, 200 mg after breakfast and 200 mg after dinner, for one week, and thereafter they went into a three-week break (pulse). Patients were examined clinically and mycologically every month before the administration of each pulse. The patients found to be clinically and mycologically active, received another itraconazole pulse. The patients who experienced adverse reactions or laboratory test abnormalities were withdrawn from the protocol and switched to a different treatment.

Patients who attained clinical and mycological cure (with negative cultures) were followed up for 6 months-one year after the last dose of the medication. Cure was considered as no clinical activity and negative cultures.

Results

The patients received variable pulses of itraconazole, with a minimum of 2 and a maximum of 5 pulses, and a mean of 3.5 months (n = 4 patients). Patient number 5 (table 1), received two itraconazole pulses and reported a significant clinical improvement, but was lost to follow-up and therefore her treatment outcome was unknown and was considered as improvement. None of the patients experienced laboratory test abnormalities during treatment. No patient reported side effects throughout the course of therapy (figures 1 and 2).
Table 1 General data of the study

Discussion

For many years the treatment of sporotrichosis consisted of potassium iodide (KI), given orally as a concentrated solution; it has high cure rates of up to 89% [9], and is inexpensive; however, it cannot resolve all cases, e.g., the cutaneous hematogenous and the systemic (pulmonary and disseminated) cases, as well as those that occur in immunocompromised patients, given that it is not an antifungal agent. Its mechanism of action remains unknown, but it is thought to work as an immunostimulating agent [1, 5-8, 10]. Another drawback of KI is its side effects; rates as high as 40% [10] have been reported, with the following most common side effects: metallic flavor, gastritis, headache, vomiting and, exceptionally, it may cause iodism, with symptoms that include runny nose, crying, salivation and arthralgias. It may also cause maculopapular rash, eosinophilia and angioedema [1, 5, 10].

Most of the common antifungals have been used to treat sporotrichosis, i.e., amphotericin B (for serious and disseminated cases), griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine [1, 4, 5, 10]. Some authors consider itraconazole as one of the drugs with the best results, given the appropriate in vitro susceptibility of S. schenckii to it, under minimum inhibitory concentrations (MIC) ranging from 0.1 to 1.0 μg/L [10-12], as well as its clinical and therapeutic results, and few side effects. It is considered by some as the drug of choice and by others as first-line therapy [1, 4, 6].

Itraconazole is a triazole derivative, usually given orally, with some important pharmacological properties; it is rapidly absorbed and is easily distributed to the skin, hair, nails, and subcutaneous cell tissue [13, 14]. Undoubtedly one of its major pharmacological properties is being considered as a depot or reservoir drug, which allows prescribing high doses that last for a certain period of time [15, 16]. In fact, intermittent or pulse therapy resulted from this property; it is aimed basically at treating onychomycosis and based on the fact that one week of 400 mg/day doses can maintain MICs for virtually one month; so when given for 3-4 months, the drug concentrations can be maintained for long enough [13-16]. Taking advantage of this feature of itraconazole, we decided to administer the drug intermittently to treat sporotrichosis, given that the latter is a relatively easy-to-treat subcutaneous mycosis and the causative fungus is drug-susceptible [11, 12]. Experiences with this drug given as continuous therapy have been reported in the literature. The first report of the use of itraconazole for cutaneous sporotrichosis was a communication by Restrepo et al. [17], who treated 17 patients at 100 mg/day doses for 90-180 days, with a 100% cure rate. Currently there are a number of communications of both immunocompetent and immunocompromised patients. Most authors believe that the most appropriate dose is 200 mg/day until clinical cure occurs [18-23]. Itraconazole has also been reported as successful and safe in children, with the most commonly used dose ranging between 25 and 100 mg/day. The recommended dose for children is 5 mg/kg/day; it is often difficult to administer itraconazole as capsules to children, but the oral solution is currently available in many countries [10, 24, 25].

This is the first study testing itraconazole pulses to treat sporotrichosis. However, this same intermittent regimen has recently been reported in the treatment of chromoblastomycosis [26], another subcutaneous mycosis much more difficult to treat than sporotrichosis. Our results with itraconazole given as pulses (one week per month) are quite similar to the ones obtained with continuous therapy, i.e., at 200-300 mg/day doses. One of the advantages of this regimen is that the intermittent treatment is reduced approximately to half the total dosage of itraconazole, especially if we compare with the scheme of 200 mg/day, with the same end results and time period. According to our results, 4/5 patients (80%) achieved clinical and mycological cure. Case number 4 (table 1) achieved cure after only two pulses; this rapid response was probably due to the fact that the patient had the fixed cutaneous variety, which usually responds more easily to various treatments [5, 24]. The remaining cases were cutaneous lymphatic, and responded after a mean of 3.5 pulses. Undoubtedly, it would have been useful to measure the levels of itraconazole in the skin after pulse and decay times. We would have obtained relevant data regarding the status of the medication in the skin; however we currently do not have those techniques available.

This type of therapy may be suggested for cutaneous sporotrichosis because these cases responded well, but we do not consider it appropriate for extracutaneous cases (pulmonary and disseminated), which warrant continuous therapy. None of the patients had side effects and the laboratory tests remained within the normal ranges. It is important to emphasize that this type of therapy should not be used in patients with gastric or liver disorders, or who are on treatments that could cause drug-drug interactions [15].

We consider this as a new treatment choice for sporotrichosis that reduces the total treatment dose and produces cure rates similar to other therapies. The pulse or intermittent therapy has the advantage of being more economic when compared to continuous therapy, since we are able to reduce the total dosage. The drawback of this report is that it is a small series of clinical cases, and therefore an increase in the number of cases would give us more precise information about the use of intermittent itraconazole. Moreover, it is also be important to know whether the strains isolated elsewhere have a similar response to this therapy.

Acknowledgements

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