Indian Journal of Paediatric Dermatology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 21  |  Issue : 4  |  Page : 259--263

Effectiveness, safety, and tolerability of itraconazole oral solution in pediatric dermatophytosis


M Ramesh Bhat, Durga Satheesh, Jyothi Jayaraman 
 Department of Dermatology, Venereology and Leprosy, Father Muller Medical College, Mangalore, Karnataka, India

Correspondence Address:
Dr. Durga Satheesh
503, Colaco Court Appartment, Old Kankanady Road, Kankandy, Mangalore DK District - 575 002, Karnataka
India

Abstract

Introduction: Cutaneous mycosis is one of the most common dermatological conditions seen in children. In the recent past, there has been an increased incidence and unresponsiveness to various antifungal agents. Itraconazole is an effective and safe antifungal agent used, especially in adults; however, there are only a few studies in the literature for the treatment of dermatophytosis in children with oral itraconazole solution. Objective: The objective of this study is to assess the safety, effectiveness, and tolerability of oral itraconazole solution in children with recurrent and extensive dermatophytoses. Methods: This is a hospital-based prospective, longitudinal, open-labeled study conducted in a tertiary care hospital over a period of 3 months at the Department of Dermatology Venerology and Leprosy. A total of 30 children with recurrent and extensive dermatophytoses were recruited for the study. All were assessed for history, clinical features, and potassium hydroxide (KOH) mount for fungus. Itraconazole oral solution was given at a dosage of 5 mg/kg body weight for a duration of 4 weeks and evaluated for safety, effectiveness, tolerability, and mycological cure (KOH mount) after 4 weeks. Results: There were 30 cases in the study comprising 18 males and 12 females. The age group 6–10 years constituted a maximum number of cases. All of these cases had more than 10% body surface area involvement. Twenty-six patients had both clinical and mycological cure, whereas four patients still demonstrated fungal elements on KOH examination. All patients demonstrated excellent safety and tolerability except one who complained that the preparation was unsavory. Conclusion: Oral itraconazole solution is effective in chronic and recurrent dermatophytoses in children.



How to cite this article:
Bhat M R, Satheesh D, Jayaraman J. Effectiveness, safety, and tolerability of itraconazole oral solution in pediatric dermatophytosis.Indian J Paediatr Dermatol 2020;21:259-263


How to cite this URL:
Bhat M R, Satheesh D, Jayaraman J. Effectiveness, safety, and tolerability of itraconazole oral solution in pediatric dermatophytosis. Indian J Paediatr Dermatol [serial online] 2020 [cited 2020 Oct 22 ];21:259-263
Available from: https://www.ijpd.in/text.asp?2020/21/4/259/296856


Full Text



 Introduction



Cutaneous mycosis is one of the most common fungal infections caused by anthropophilic and zoophilic dermatophytes.[1] Common species of fungi that affect skin are (1) Microsporum, (2) Trichophyton, and (3) Epidermophyton.[2] Recently, there is an abrupt increase in dermatophytic infections in adults and children.[3] It has also been observed that Trichophyton mentagrophytes is the most common species identified in these infections.[4]

Itraconazole is an orally active triazole antifungal with lipophilic properties.[5] Itraconazole is used as a broad-spectrum antifungal agent against dermatophytes, yeasts, and molds since 1980. Globally, itraconazole is available as oral (capsule and solution) and intravenous formulation.[6] At present, dermatophytosis in India is difficult to treat, and itraconazole is the widely used drug for the management, considering the low response rate for previously used drugs such as terbinafine, fluconazole, and griseofulvin. Even though dermatophytosis in children is rare compared to adults, in the present epidemic, it is seen in children as well with increasing frequency, and the management of these recurrent and resistant dermatophytoses is a therapeutic challenge. Even though itraconazole in capsule form is widely used, it is difficult to administer it in children considering the size of the capsule. Itraconazole oral solution is used in oropharyngeal and esophageal candidiases in immunocompromised patients.[7]

In view of the recent availability of itraconazole oral solution, it can be effectively administered with ease in children. It has frequently been used in pediatric cases of superficial and systemic fungal infections, although it has not been approved by the Food and Drug Administration. More safety data are required, however, in the use of oral solution formulation to treat dermatophytosis in children. Itraconazole seems to be effective and safe for the treatment of pediatric dermatophytosis, and the spectrum of adverse events reported is comparable with adults and relatively infrequent.[8] However, since there are only a few studies in the literature for the treatment of dermatophytosis in children with oral itraconazole solution; this study is conducted.

 Methods



This was an open, prospective longitudinal, study conducted to study the effectiveness and tolerability of itraconazole oral solution in pediatric dermatophytosis. A total of 30 children in the age group of 1- 12 years clinically diagnosed cutaneous dermatophytosis and confirmed with potassium hydroxide (KOH) 10% wet mount preparation were included in the study. The study was conducted from June to September 2019. Only 30 patients were selected as there were only very few studies conducted with oral itraconazole solution for dermatophytosis in children in India. The study was approved by the institutional ethical committee with an instruction to include only recurrent and extensive dermatophytoses and registered with CTRI (CTRI/2019/05/019139). Children with recurrent (past history of more than one episode of same disease which was treated) or extensive (>10% body surface area [BSA]) dermatophytosis were included. Oral and written consent were taken from parents/guardian. At the time of enrollment, detailed predesigned proforma was filled with detailed history in relation to age, sex, duration of illness, prior treatment, sites of involvement, and BSA and family history of fungal infections, which were elicited and recorded. All the children were subjected to KOH mount examination. Scales from the lesion were scraped off using a glass slide and were observed under low-power magnification (×10) after mounting on a glass slide with 10% KOH wet preparation. This was repeated after 2 weeks and 4 weeks from the date of the first visit. Itraconazole oral solution (5 mg/kg body weight/day) one hour after food, was administered for 4 weeks.

Patients were followed up after 2 and 4 weeks, both clinically and along with KOH mount preparation. Patients were followed up for clinical, mycological cure (KOH wet mount preparation), and the tolerability of itraconazole oral solution. Collected data was analyzed by frequency and Chi-square test.

 Results



Data were analyzed using frequency test and Chi-square by the Statistical Package for the Social Sciences (SPSS IBM; version 25.0; Chicago, Illinois, USA). A total of 30 patients were enrolled in the study, of which 12 (40%) were females and 18 (60%) were males. A maximum number of cases were from the age group of 6 to 10 years; the youngest patient was 1 year 3 months old and the eldest was 12 years old. Duration of the infection was up to 3 months in 14 cases, between 4 and 6 months in 10 cases, 6 months to 1 year in 5 cases, and more than 1 year in only one patient [Figure 1]. Eight patients had involvement of >20% BSA. The primary effectiveness parameter was clinical improvement with relief of symptoms, and the secondary effective parameter was mycological improvement with KOH mount results for the presence or absence of fungal hyphae. Majority of the patients had itching (29 cases), and there were associated erythema in 26 patients, pigmentation in 24 patients, and scaling in all of the patients. All the patients had a spreading infection, and history of recurrence was seen in 22 patients. Twenty-six patients had a previous history of medication for dermatophytosis, of which nine had self-medication. Eighty percent of the patients had a family history of similar infection. Majority of the patients (14) had the infection in the groin folds, and other sites involved along with the percentage of involvement are mentioned in [Figure 2]. KOH mount was done on baseline, 2nd week, and 4th week (endpoint) of commencing the study; all cases were positive for fungal hyphae by KOH mount on baseline, and it came down to 4 positive KOH mount by week 4. KOH mount was positive in 18 patients in the 2nd week and 4 patients after the 4th week (endpoint) [Figure 3]. 86.7% of the cases showed clinical improvement of 71%–90%, and only four patients showed an improvement of 50%–70%. Ninety percent of the patients showed complete clinical cure in the form of the absence of itching, scaling, and erythema [Figure 4]a, [Figure 4]b; however, postinflammatory hyperpigmentation was observed in most of the patients [Figure 5]a, [Figure 5]b and [Figure 6]a, [Figure 6]b. After the completion of treatment schedule, three patients still had scaling and mild inflammation and they demonstrated KOH positivity even after 4 weeks. One more patient also who had clinical improvement also showed KOH positivity. LFT was done in 10 patients before and after the treatment, and in all the patients, it was within the normal range. All the patients tolerated the oral solution well except one who complained of a bad taste. None of the patients complained of symptoms suggestive of gastrointestinal upset.{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}{Figure 6}

 Discussion



Dermatophytic infections of the skin and its appendages are a common occurrence, yet their treatment is challenging in pregnant women, children, and the elderly age group. In limited cutaneous disease, treatment with topical azoles is known to be effective. Terbinafine is the preferred oral agent in elderly population for the treatment of extensive cutaneous disease and onychomycosis due to its lack of cardiac complications and lesser incidence of drug interactions. There is a rising prevalence of dermatophytosis in tropical countries.[1],[9] Literature suggests that Trichophyton rubrum and T. mentagrophytes complex are the most frequent agents affecting skin and nail, whereas Trichophyton tonsurans, Trichophyton violaceum, and Microsporum canis are the predominant pathogens responsible for tinea capitis.[10] A study done in our institute in 2005–2006 by Surendran et al. has found that T. rubrum was predominant species, followed by T. mentagrophytes, in 100 cases and was more commonly seen in male gender.[11] However, a recent unpublished study conducted in our institute comprising 345 cases showed T. mentagrophytes (59.5%) as the predominant species, followed by T. rubrum (27.97%) and T. tonsurans (11.92%), respectively. Among which, 50 cases were tested for drug resistance, and terbinafine showed a higher minimum inhibitory concentration (MIC) value of above 0.5 μg/ml in 10 cases. In 36 patients (among 50) who were positive for T. mentagrophytes, 7 showed a higher MIC value of 0.5 μg/ml. Similarly, another study conducted among 256 patients by Mahajan et al. has also commented on the changing pattern of T. mentagrophytes being the predominant species as well as itraconazole being the most effective drug among other antifungals.[12] The effective options in children include griseofulvin, terbinafine, itraconazole, and fluconazole in addition to topical antifungals.[13] The effectiveness of these systemic agents has been established in several randomized controlled trials.[14],[15],[16]

A study done by Gupta et al. in 2003 showed that the dosage of itraconazole of 3–5 mg/kg/day is safe and effective for superficial fungal infections in children. The study also states that, compared to capsule, oral solution will have more gastric symptoms.[7] Another study by De Repentigny et al. states that the oral solution of itraconazole 5 mg/kg/day for 2 weeks provides a potential therapeutic plasma level but is substantially low than obtained in adult patients. It also has a potential in treatment and prophylaxis of mucosal and invasive fungal infections in children.[5] A study by De Doncker et al. states that a 1-week pulse of itraconazole 200 mg for tinea infection of the skin resulted in 90% clinical response and 80% mycological cure rate. However, in Indian scenario, more pulses are required. It also says that higher levels of itraconazole are seen in sebum and stratum corneum.[6] Of the 30 patients enrolled in the study who received oral itraconazole as treatment, 86.7% of the cases showed clinical improvement of 71%–90%, whereas only 1 patient showed an improvement of <50%. This is similar to the finding of a comparative trial of ultramicronized griseofulvin and itraconazole which reported a significantly better outcome with 2 weeks of itraconazole therapy.[13]

In children, itraconazole has demonstrated an excellent safety profile, with frequency of adverse effects being reported in the range of 1.9%–3.5%. The most common adverse events include gastrointestinal disorders (nausea, vomiting, and abdominal pain), rash, dizziness, sleepiness, headache, and abnormality in LFT. These events are mild and transient. This cannot be stated since the liver function tests were not done in all the 30 patients. and tolerability except for one who complained that the preparation was unsavory. LFT values were normal before and after in all the 10 patients who consented for the blood examination. In most of the trials and case reports, where itraconazole has been used to treat dermatophytosis, laboratory testing has not been performed on a regular basis. However, where available, reports suggest that alteration of LFT is an infrequent occurrence.[8]

 Conclusion



There is an increasing trend of recurrent, resistant, and relapsing dermatophytoses in India, both in adults and children. T. mentagrophytes is the predominant pathogen and at times does not respond to topical antifungals and systemic agents such as terbinafine, fluconazole, and griseofulvin. However, the use of oral itraconazole solution in recurrent and widespread dermatophytoses helps in managing these cases, but the treatment of dermatophytosis in pediatric population needs a cautious approach. Our study shows that oral itraconazole is both effective and Cannot be claimed on the basis of this study in the treatment of dermatophytosis in children.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

We would like to thank Alkem Laboratories Limited for supplying itraconazole oral solution.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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