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ORIGINAL ARTICLE
Year : 2022 | Volume
: 42
| Issue : 1 | Page : 45-52
Therapeutic efficacy of three systemic antifungals in onychomycosis: a randomized clinical trial
Emad A Taha1, Ahmed Mohamed Moharam2, Amany Morgan Ladeed3, Yasmin M Tawfik1, Radwa M Bakr1
1 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Assuit University, Assiut, Egypt
2 Mycology, Botany and Microbiology Department, Faculty of Science, Assiut University, Assiut, Egypt
3 Resident in Assuit Dermatology Clinic, Assiut, Egypt
Correspondence Address:
MD Radwa M Bakr
Lecturer of Dermatology, Venereology and Andrology Department, Faculty of Medicine, Assiut University, Assiut, 71515
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejdv.ejdv_4_21
Background Onychomycosis is a nail fungal infection that significantly affects the patient’s quality of life. It represents a treatment challenge for dermatologists.
Aim The aim was to compare the efficacy of pulse therapy of itraconazole, fluconazole, and terbinafine in the treatment of onychomycosis.
Patients and methods Sixty patients clinically and mycologically diagnosed with onychomycosis were included in this study. Patients were randomly divided into three groups: group A received itraconazole (400 mg/day for 1 week/month); group B received fluconazole (300 mg/week); and group C received terbinafine (500 mg/day for 1 week/month). All patients received the treatment for 3 months and were followed up for another 3 months. They were evaluated clinically by photography, mycologically (microscopy and culture), and by the ‘Naildex score questionnaire’.
Results The clinical, mycological, and complete cure rates were the highest among group A (80, 70, and 70%, respectively), followed by group C (60, 55, and 55%, respectively) and finally group B (50, 35, and 35%, respectively), with no statistical difference between them. Also, group A showed greater improvement in the nail function index compared with the other two groups.
Conclusion Pulse therapy of itraconazole, terbinafine, or fluconazole was effective in the treatment of onychomycosis with increasing patient compliance. The best response was achieved with itraconazole, followed by terbinafine and finally fluconazole.
Keywords: fluconazole, itraconazole, naildex, onychomycosis, pulse therapy, terbinafine
Onychomycosis is referred to as nail infection caused by dermatophytes, yeasts and nondermatophytic molds (NDM). It affects any part of the nail unit, including the nail bed, nail matrix, or nail plate [1]. Clinically, it is characterized by roughening and thickening with discoloration of the nail plate. It represents about 30% of all superficial fungal skin infections and 50% of all nail diseases [2]. The resulting disfigurement affects the patient’s self-esteem and has a negative impact on the quality of life (QoL) [3].
Treatment of onychomycosis is considered a challenge for dermatologists because of the high cost of therapy, poor patient compliance, the deep-seated nature of the fungi within the nail plate and the slow growth of the nail plate, all requiring a long time to achieve effective results [4]. Another challenge is the increasing resistance to systemic antifungal treatment nowadays [5].
Terbinafine, itraconazole, and fluconazole represent a turning point in the treatment of onychomycosis, substituting older drugs such as griseofulvin. They are administered either continuously on a daily basis or as pulse therapy (1 week on, 3 weeks off every month) [6]. The latter may be preferred as it decreases the total drug exposure with fewer adverse effects, minimizes the treatment duration, reduces the treatment costs and improves the patient compliance, hence lowering the chance of developing drug resistance [7].
To date, limited studies are available comparing the therapeutic effect of more than two drugs in the treatment of onychomycosis [8],[9]. We carried out this study to compare the efficacy of pulse therapy of three systemic antifungal drugs (itraconazole, fluconazole and terbinafine) in the treatment of fingernail onychomycosis on the basis of clinical, mycological improvement, and QoL.
Patients and methodsStudy design
This single-blinded randomized clinical trial study comprised a total of 60 patients clinically diagnosed with fingernail onychomycosis and confirmed by mycological examination (direct microscopic examination and culture) recruited from the outpatient clinic of the Department of Dermatology, Venereology and Andrology, Assiut University Hospital, from January 2018 to June 2019. The study was approved by the Institutional Ethics and Research Committee of Faculty of Medicine, Assiut University. The study protocol was explained to the patients and a signed informed consent was obtained before being included in the study. A clinical trial registry was done on ClinicalTrials.gov with Identifier: NCT03171584.
Patients with fingernail onychomycosis of different sexes and ages, resistant to previous topical treatment, were included in the study.
Patients with previous nail trauma, 20 nail dystrophy, keratinization disorders such as psoriasis, patients who had received any systemic or topical antifungals in the previous 3 months, those with chronic medical or cutaneous diseases, those receiving immunosuppressive drugs or drugs affecting the nail color or growth, pregnant and lactating females were excluded from this study.
Treatment procedure
The recruited patients were randomly assigned (the method used for allocation concealment was sealed envelopes) into three treatment groups according to the systemic antifungal used.
Group A (20 patients): the patients were treated with pulse therapy of oral itraconazole (Itracon 100 mg) two capsules administered twice daily at a dose of 400 mg/day for 1 week per month for 3 months [10].Group B (20 patients): the patients were treated with pulse therapy of oral fluconazole (Fungican 150 mg) two capsules in a weekly dose of 300 mg for 3 months [11].Group C (20 patients): the patients were treated with pulse therapy of oral terbinafine (Trerbi 250 mg) two tablets at a daily dose of 500 mg for 1 week every month for 3 months [10].Assessment of the efficacy of the therapeutic procedure
The treatment efficacy was assessed based on clinical and mycological improvements in addition to the QoL.
Photographs were taken before treatment, monthly for 3 months and 3 months after the end of each treatment protocol. All photographs were taken using a Panasonic digital camera (DMC-FH2, 14 megapixels; Panasonic, Osaka, Japan), using identical camera settings, lighting, and patient positioning. The improvement was assessed by two blinded dermatologists for each patient after completion of the treatment by comparing the photos before and after treatment.
Mycological examination of the nails was performed by potassium hydroxide (KOH) examination and culture on Sabouraud’s dextrose agar (SDA) at baseline and six months after starting the therapy. The surface of the nail was cleaned with 70% alcohol before taking the sample. The specimens were obtained from clinically affected nails, by vigorous scraping of the nail bed, the underside of the nail plate and the hyponychyum (the site of sample collection differs according to the clinical type of onychomycosis). Each sample of the fingernail was divided into three parts. One part was mounted in a mixture of 20% KOH/40% dimethyl sulfoxide for direct microscopic examination (dimethyl sulfoxide increases the sensitivity of the preparation and softens keratin). The preparation was warmed gently and then left for 20 min before examination. The second part of the nail sample was cultured on SDA that was premixed with chloramphenicol and cycloheximide (to prevent bacterial growth and fast-growing molds) and incubated at 30°C, providing the chance for growth of dermatophytic fungi. The third part was cultured on SDA without cycloheximide to allow good growth of molds. Agar plates were reviewed for growth daily up to 4 weeks as fungi are slowly growing pathogens. The presence of growth on the agar plate is subjected to microscopic examination for species identification. Identification of fungal cultures was based on macroscopic and microscopic characteristics according to descriptions of medical fungi. The isolated yeasts were identified by culturing on a chromogenic medium [12].
Clinical cure was considered when greater than 75% of the mycotic nail became normal and healthy appearing. Mycological cure was considered when both microscopy under KOH examination and culture turned negative at the end of the follow-up period.
The QoL questionnaire (Naildex) was assessed before and after treatment. It is a baseline questionnaire consisting of 15 items specific to the nail and it represents a concise, valid, reliable, and responsive instrument for measuring the burden of skin disease for patients with onychomycosis.
The scale scores of symptom, emotion, and function were calculated by the average of the item scores, which were scored on a 0–100 scale, where: 0=never; 25=rarely; 50=sometimes; 75=often; and 100=all the time. The naildex score was calculated as the sum of the score of 15 questions ranging from a score of 0 to 1500 [13].
Follow-up assessment
The patients were followed up after 3 months of completion of each drug regimen and re-evaluated clinically by photography, mycologically (KOH and culture) and by reassessment of the ‘Naildex score questionnaire’.
Statistical analysis
Data management and data analysis were carried out using International Business Machines (IBM)-SPSS version 23 (Statistical Package for the Social Sciences). Mean±SD, when appropriate, described quantitative data. χ2 and exact tests were used to compare between qualitative variables. Analysis of variance/post-hoc with Bonferroni correction was used to compare quantitative variables between groups in case of parametric data and the Kruskal–Wallis test for nonparametric data. P-value was considered statistically significant when P less than 0.05.
ResultsAll recruited patients (60 patients) completed the treatment protocol and were included for the final analysis. Their ages ranged from 20 to 70 years, with a mean±SD of 39.05±11.08 years. There were 56 female patients (93.33%) and four male patients (6.67%). Thirty patients (50%) were from rural areas and 50 patients (83.33%) were not working (83.33%). The sociodemographic data of each group are presented in [Table 1].
Distal lateral subungual onychomycosis (DLSO) was the predominant type (28/60) among the studied patients (47%), while 18/60 patients (30%) suffered from Candidal onychomycosis in the form of a dystrophic nail and paronychia and only 14/60 patients (23%) presented with total dystrophic onychomycosis. There was no statistical difference between the three treatment groups in their baseline characteristic data before treatment as shown in [Table 1].
The mycological analysis of the nail samples revealed the isolation of 17 fungal species belonging to 10 genera ([Table 2]). Candida was the most prevalent genus, affecting 35 patients out of 60 (58.3%). It was represented by three species, of which Candida albicans was responsible for 46.7% of nail infections, followed by Candida parapsilosis and Candida krusei (8.3 and 3.3%, respectively). Molds alone affected eight cases (13.3%), of which 6 cases were due to Aspergillus spp. The remaining 17 cases of onychomycosis (28.3%) were due to infections by a mixture of two molds belonging to Aspergillus and Penicillium, two yeasts attributed to Candida and Rhodotorula or a combination of yeasts and molds (e.g. Candida and Acremonium, Candida and Fusarium, or Geotrichum and Scopulariopsis).
Table 2 Incidence of fungal species isolated from cases of onychomycosisThe clinical, mycological and complete cure rates were the highest among group A (80, 70, and 70%, respectively), followed by group C (60, 55, and 55%, respectively) and finally group B (50, 35, and 35%, respectively), with no statistical difference between them ([Table 3] and [Figure 1],[Figure 2],[Figure 3]).
Figure 1 Complete cure in a patient with fingernail onychomycosis (a) before treatment and (b) after pulse therapy with itraconazole.
Figure 2 Complete cure in a patient with fingernail onychomycosis (a) before treatment and (b) after pulse therapy with fluconazole.
Figure 3 Complete cure in a patient with fingernail onychomycosis (a) before treatment and (b) after pulse therapy with terbinafine.The decrease in Naildex was significant with itraconazole compared with both fluconazole and terbinafine ([Table 4]), which mean that the itraconazole group showed greater improvement in the nail function index compared with the other two groups.
Table 4 Comparison of improvement according to naildex in the three studied groupsThere was a positive correlation between the Naildex score and the duration of fungal nail infection (r=0.333, P=0.009).
DiscussionOnychomycosis is the most common nail disease and, if left without treatment, it can lead to pain, discomfort, infection, and subungual ulceration. The disfigured nails usually have psychosocial and emotional impacts that significantly affect the QoL [14]. Few studies were carried out to illustrate the comparative efficacy of systemic antifungals in case of onychomycosis, with a sparsity of randomized clinical trials [9],[10].
Our study aimed to compare the efficacy of three systemic antifungal drugs in proven hand nail infection with culture and we assessed the QoL in onychomycosis patients using the Naildex nail questionnaire. We focused on fingernail infection unlike other studies that were carried out on toenail onychomycosis [8] or those that were carried out on both fingers and toenails [10],[15]. The age range in our study was from 20 to 70 years, with a mean of 39 years, which is similar to the age range and mean in other studies [16],[17],[18]. The patients in this age group have higher exposure to risk factors for nail infection and are more conscious about discoloration and disfigurement of their nails. In our study, 95% of the patients were females, while only 5% were males. The condition is predominantly seen in females as housewives due to working in wet environment [17],[18],[19]. Also, the fact that females are more concerned about their cosmetic appearance and disfigurement in nails can affect their self-esteem, and this could be the reason for the predominance of females in this study.
DLSO was the most common pattern of onychomycosis in our study (47%), followed by candidal onychomycosis (30%); this was in agreement with other studies that reported DLSO to be the most common pattern of onychomycosis [17],[20],[21].
Candida species was the most common etiological agent (58.33%). This was similar to other studies [17],[19] that reported that yeasts were the most common pathogens isolated in their patients, but in contrast to Cengiz et al. [21], who reported that dermatophytes were the most common pathogens. Wijesuriya et al. [22], reported that NDMs were the most common isolated pathogens. Many factors are responsible for this variation such as the difference in local environmental conditions, varied diagnostic procedures, the degree of exposure to the pathogens and the variety of the causative organism that differs according to their geographical location. Gupta et al. [23] reported that in Western countries, 80–90% of onychomycosis cases are caused by dermatophytes, with 5–17% due to yeasts and 2–3% due to NDMs. In southern European countries, dermatophytes were detected in 40–68% of cases, with 21–55% of cases due to yeasts. In Asian and Middle Eastern countries, dermatophytes are the causative organisms in 40–48% of cases, 43–46% due to yeasts and 8–11% due to NDM-related infections. In Africa, onychomycosis-related infections are predominantly caused by yeasts.
In our study, group A, which was treated by pulse itraconazole (400 mg), showed clinical cure of 80%, and mycological and complete cure of 70% for each. Similar results were reported by Arca et al., who revealed clinical cure in 77.8% of patients, and mycological and complete cure in 61.1% equally [8]); Ankani, [10] who reported clinical cure in 70% of patients and mycological cure in 87%; and Mishra et al. [15], who detected a clinical cure rate of 82% and mycological cure rate of 90%. Another study carried out by Tosti et al. [24] revealed mycological cure in 75% of patients.
Itraconazole is highly effective in the treatment of dermatophytes, yeast, and NDM infections of the nails. It has the ability to rapidly penetrate the nail within 7 days of starting treatment (reaching the distal end of the nail within 2 weeks of starting therapy), remains in the nail for long periods (up to 9 months post-therapy) and can be quickly eliminated from the plasma; thus, it is an ideal drug for use as intermittent therapy [6],[15].
Group B, which was treated by pulse fluconazole (300 mg/week), showed a clinical cure of 50%, and mycological and complete cure of 35% each. Other studies showed similar results on using fluconazole (150 mg/week) [8],[9],[25]. Vora et al. [9] detected a clinical cure of 33.33%; Arca et al. [8] reported a clinical cure in 37.5% of patients, and mycological and complete cure in 31.2% equally. Havu et al. [25] observed complete clinical cure rates of 21% and 32% upon using fluconazole for 12 and 24 weeks, respectively. Higher cure rates were reported in other studies using fluconazole for a longer treatment duration (6–12 months vs 3 months in the present study) [26],[27]; however, the risk of side effects with this long-term treatment duration and subsequently poor patient compliance should be considered.
Group C, which was treated by a pulse regimen of terbinafine (500 mg), showed a clinical cure rate of 60%, and mycological and complete cure rates of 55% each. Almost similar results were obtained by other studies that used the same pulse regimen [10],[15],[16],[24]; Sprenger et al. [16] showed a total cure rate of 71.43%. Ankani [10] showed clinical and mycological cure rates of 85 and 90%, respectively, and the same was observed by Mishra et al. [15], with clinical and mycological cure rates of 79 and 87%, respectively. Another study by Tosti et al. [24] showed mycological cure in 80% of patients. Our relatively lower cure rates may be explained by the fact that most of the previous studies treated mainly dermatophytes, while in our study, the majority of organisms were yeasts. Although all fungus species respond to terbinafine, the best results were achieved when treating dermatophytes [15].
Terbinafine is an allylamine drug that prevents the biosynthesis of ergosterol (necessary for fungal cell membrane synthesis) by the inhibition of squalene epoxidase enzyme. The drug has been found in the nail plate after stopping treatment for 30–36 weeks [15].In the present study, on comparing the three groups, group A (Itraconazole) showed the highest results, followed by group C (Terbinafine) and finally group B (Fluconazole), with no significant difference between them. A few previous studies compared the efficacy of these three drugs in the treatment of onychomycosis and reported that itraconazole and terbinafine show comparable results, followed by fluconazole [8],[9]. Most of the published studies compared the efficacy of only two drugs; previous studies that compared terbinafine with itraconazole observed no significant difference between them in the clinical and mycological cure. Mishra et al. [15] obtained superior results with itraconazole, while Ankani [10] reported better results with terbinafine. These variations in the results are mostly due to the differences in the causative organism in each study. It is well known that both drugs act as fungicidal and fungistatic agents [28]. Although terbinafine is primarily effective against dermatophytes, and less effective against yeasts and molds, itraconazole achieved similar cure rates for dermatophytes as terbinafine; furthermore, it is more effective in cases of onychomycosis caused by molds and candida [15].
We assessed the QoL using the naildex score, with a higher improvement in the nail function index in group A treated by itraconazole compared with the other two groups. To the best of our knowledge, no published studies used this nail function index to compare the efficacy of the three systemic antifungals in the case of onychomycosis. Warshaw et al. [29] used the treatment satisfaction scale from Lubeck’s questionnaire in their study of terbinafine versus pulsed-dose itraconazole and reported greater satisfaction with terbinafine.
In our study, there was a strong correlation between the naildex score and duration of nail infection similar to Warshaw et al. [13], who reported in their study that higher naildex scores for toenails were correlated with duration of disease.
In conclusion, pulse therapy of systemic antifungals is very effective in the treatment of fingernail onychomycosis with favorable patient compliance and adherence to the treatment due to the shorter duration of the treatment protocol. The best response was achieved with itraconazole, and it can be recommended for use as first-line treatment in cases of candida or mixed infections and terbinafine can be considered a good alternative.
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Conflicts of interest
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References
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