|Year : 2019 | Volume
| Issue : 4 | Page : 253-260
|A randomized, double-blind study of amorolfine 5% nail lacquer with oral fluconazole compared with oral fluconazole alone in the treatment of fingernail onychomycosis
Somodyuti Chandra1, Karan Sancheti1, Indrashis Podder2, Anupam Das3, Tushar Kanti Sarkar1, Moitreyee Chowdhury4, Amrita Sil5, Susmita Bhattacharya6, Nilay Kanti Das7
1 Department of Dermatology, Medical College, Rampurhat, Birbhum, West Bengal, India
2 Department of Dermatology, Sagore Datta Medical College, Rampurhat, Birbhum, West Bengal, India
3 Department of Dermatology, KPC Medical College, Rampurhat, Birbhum, West Bengal, India
4 Department of Biochemistry, Medical College, Rampurhat, Birbhum, West Bengal, India
5 Department of Pharmacology, Rampurhat Government Medical College, Rampurhat, Birbhum, India
6 Department of Microbiology, Kalyani Medical College, Nadia, West Bengal, India
7 Department of Dermatology, Bankura Sammilani Medical College, Bankura, West Bengal, India
|Date of Web Publication||5-Jul-2019|
Department of Pharmacology, Rampurhat Government Medical College, Rampurhat, Birbhum - 731 224, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: It is a challenge to treat onychomycosis due to frequent treatment failures and relapses. Systemic and topical therapies need to be combined to improve cure rates. Antifungal susceptibility might play a role in the treatment resistance of onychomycosis. Aims: To compare the safety and effectiveness of amorolfine 5% nail lacquer + oral fluconazole versus only oral fluconazole in the treatment of fingernail onychomycosis. Methodology: In this double-blind trial (CTRI/2015/02/005369), patients were randomized (1:1) into amorolfine 5% nail lacquer + fluconazole and dummy lacquer + fluconazole. Treatment was given for 3 months with monthly follow-ups. Antifungal sensitivity was carried out for Candida. Effectiveness was assessed by reduction in the number and percentage area of nails involved and mycological cure. At the end of 3-month treatment period, the association between drug sensitivity and treatment response was explored for the Candida infections. Results: Among 30 study participants, the combination group showed significantly lower number of nail involvement (P = 0.004) and percentage nail involvement (P = 0.005) than only fluconazole group. Pretreatment fungal culture showed a comparable number of dermatophytes, Candida, Aspergillus in both the groups. Sensitivity testing was done for the isolated Candida species. Antifungal sensitivity for Candida (n = 11) was tested, and 8 (72.7%) of the organisms were sensitive to fluconazole (minimum inhibitory concentration [MIC] 1.25 ± 1.19 μg/ml), 100% were sensitive to itraconazole (MIC 0.0726 ± 0.021 μg/ml), and 3 (27.3%) were susceptible-dose dependent (S-DD) to fluconazole (MIC 16 μg/ml). Fluconazole only group patients with Candida who showed resistance to fluconazole did not respond to therapy; however, patients in the combination group showed moderate improvement (reduction in area involvement = 55.56 ± 35.36%). Conclusion: The combination of amorolfine/fluconazole achieved a higher cure rate not only for sensitive fungus but also for those which were S-DD to fluconazole.
Keywords: Amorolfine nail lacquer, fluconazole, onychomycosis, randomized control trial
|How to cite this article:|
Chandra S, Sancheti K, Podder I, Das A, Sarkar TK, Chowdhury M, Sil A, Bhattacharya S, Das NK. A randomized, double-blind study of amorolfine 5% nail lacquer with oral fluconazole compared with oral fluconazole alone in the treatment of fingernail onychomycosis. Indian J Dermatol 2019;64:253-60
|How to cite this URL:|
Chandra S, Sancheti K, Podder I, Das A, Sarkar TK, Chowdhury M, Sil A, Bhattacharya S, Das NK. A randomized, double-blind study of amorolfine 5% nail lacquer with oral fluconazole compared with oral fluconazole alone in the treatment of fingernail onychomycosis. Indian J Dermatol [serial online] 2019 [cited 2019 Dec 8];64:253-60. Available from: http://www.e-ijd.org/text.asp?2019/64/4/253/262170
| Introduction|| |
Onychomycosis, the fungal infection of nails, causes discoloration, thickening, and separation from the nail bed. Although the prevalence of onychomycosis is about 10% in general population, it is more common in older age group due to comorbid conditions and less vascularity of the nails. Although it may seem that onychomycosis is a cosmetic problem, it can be uncomfortable and has the potential to cause paronychia and in turn pyogenic superinfection, leading to cellulitis in elderly and diabetics., The quality of life in patients diminishes as onychomycosis can be a source of embarrassment; hamper day-to-day activities especially in patients associated with cooking and wet work. Also, with the rising trend of antifungal-resistant strains of the dermatophytes and Candida, the treatment shows failures and relapses. The intrinsic nature of the nails being made from keratin makes them nonvascular, impermeable to many drugs, and the treatment duration long.
One way of improving the speed of cure and the overall rate is to combine systemic and topical treatments. Combining systemic antifungals with topical therapy may improve cure rates, prolong remission period, and reduce the duration and adverse effects of systemic therapy. It has been shown previously that the addition of topical amorolfine improved the results obtained with griseofulvin in the treatment of extensive dermatophyte-induced onychomycosis. The increased efficacy of this combination may be due to synergistic drug activity and/or complementary routes of drug penetration into the nail bed, matrix, and plate. Among the systemic antifungals, fluconazole is widely used in the treatment of onychomycosis and the price of the therapy with fluconazole is significantly lower; thus, the combination of fluconazole with topical amorolfine appears cost-effective too. This study aimed to compare the safety and effectiveness of amorolfine 5% nail lacquer with oral fluconazole versus only oral fluconazole in the treatment of fingernail onychomycosis. It explores the antifungal susceptibility pattern of the fungal element detected in the culture and its effect on the treatment outcome.
| Methodology|| |
The study was designed as a double-blind, randomized (1:1), active-controlled, parallel group trial done at the department of dermatology of a tertiary care hospital of eastern India. The patients were recruited from February 2015 to July 2015 for 6 months and followed up for another 3 months. Patients of either gender, within the age range of 18–65 years, and suffering from at least one fingernail onychomycosis with or without matrix involvement were included after mycological confirmation by KOH mount. Pregnant or lactating women, those with concomitant disease predisposing to onychomycosis (e.g., diabetes, poor peripheral circulation) or suffering from other nail conditions (e.g., psoriasis) which might interfere in the interpretation of results, those on treatment with a topical or systemic antifungal during 4 weeks preceding screening, with cardiac, hepatic, or renal comorbidities, and those having history of hypersensitivity to any of the drugs were excluded from the study. Institutional ethics committee permission was taken before the onset of the study, and written informed consent was obtained from all patients. The trial was registered with the Clinical Trial Registry, India, (CTRI) and bears the registration number CTRI/2015/02/005369.
The study participants were randomized using a computer-generated random number table in 1:1 ratio to either of the treatment arms into (oral fluconazole 150 mg + topical amorolfine nail lacquer 5%) or (oral fluconazole 150 mg + dummy lacquer). Fluconazole 150 mg (AF-150, Systopic Laboratories, Batch no. A0060214, date of manufacture 02/2014, date of expiry 01/2016) was administered once weekly for 3 months in all patients. Amorolfine 5% (Loceryl, Galderma, Batch no. 4212312, date of manufacture 09/2014, date of expiry 09/2017) or dummy lacquer (transparent nail polish of Lakmé™) was administered topically on the affected nail after filing once weekly for 3 months. Allocation concealment was done by sequentially numbered opaque sealed envelope technique. Investigator was blinded by separating the dispensing and evaluating physician. The patients were blinded by supplying amorolfine nail lacquer and dummy lacquer in identical-looking coded colored bottles [Figure 1]. Thus, double blinding was achieved. The medicines were given continuously for 3 months.
|Figure 1: Patient blinding achieved by supplying amorolfine nail lacquer and dummy lacquer in identical looking coded colored bottles|
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Visits and follow-ups
At baseline visit, patients were diagnosed clinically, informed consent was obtained, and nail clipping was taken for KOH mount, fungal culture, and determining antifungal sensitivity pattern. Routine laboratory tests such as routine hemogram, liver function test, serum urea and creatinine, and blood glucose levels were done, and medicines were dispensed as per randomization. Three follow-ups were carried out at 4 weekly intervals at 4-week, 8-week, and 12-week. At all follow-ups, the study parameters were noted, adverse reactions noted and medicines dispensed. At the last follow-up, the nail clippings were taken and baseline blood investigations were repeated to know the end of the treatment response. At all follow-ups, the empty strips of fluconazole were assessed and the bottles of lacquer were checked to assess adherence to therapy. The participants were contacted by phone calls every Sunday to impress on adherence.
The effectiveness parameters were comparison of the reduction the number of nails involved, percentage area of nail involved, and mycological cure (by KOH mount and culture), between the two treatment groups. The area of nail involvement was calculated as the product of the longest length and the longest breadth of the affected nail. The safety parameters included changes in laboratory investigations at the end of the treatment, spontaneously reported adverse events, and those adverse reactions elicited by the clinicians. Quality of life was assessed at baseline and study end in both groups by a validated vernacular version of Dermatology Life Quality Index (DLQI) (http://www.dermatology.org.uk/downloads/DLQI_Bengali. Pdf), which consisted of 10 questions, each scored between 0 and 3.
Nail clippings, KOH mount, fungal culture, and antifungal sensitivity
Nail clippings were obtained aseptically from the patients and were sent to the mycology laboratory in properly labeled, clean, sterile black envelope as soon as possible (preferably within 2 h) for fungal evaluation and antifungal sensitivity testing. Affected nail (s) was cleaned with 70% alcohol. Clippings from nail (discolored, dystrophic, or brittle) were taken as far back as possible from the free edge. Full thickness of the nail (s) was included. In white superficial onychomycosis, only the scrapings from the white spots were collected, discarding the uppermost layer.
At the laboratory, the nail clippings were kept overnight in 10% KOH. The clippings were viewed under the low power (×10) of microscope to search for the presence of branching septate hyphae and arthrospores, which indicates the dermatophytes or budding yeast cells, and thus the diagnosis of onychomycosis was made. The findings were confirmed under ×40 magnification of microscope.
After direct microscopy, all the nail clippings were trimmed down to 1 mm (approximately) and were inoculated at four sites at well-spaced intervals into Sabouraud's dextrose agar slant in McCartney's bottle containing 0.05 mg/ml chloramphenicol and 0.5 mg/ml cycloheximide (SDA-CCA), to inhibit the bacterial growth and the growth of saprophytic fungi, respectively. Then, they were incubated at both 25°C and 37°C in pairs and examined daily up to 4 weeks for evidence of growth from the edge of the planted material. If no growth appeared, the results would be declared negative after 4 weeks of incubation.
The colonies of Candida spp. were cream-colored smooth paste-like colonies on SDA [Figure 2]a. They were further identified by germ tube test and appearance of characteristic colored colonies on CHROMagar. The colonies of Candida albicans were white creamy colored and that of Candida parapsilosis are pale white colored and Candida tropicalis blue in color [Figure 2]b. C. albicans were germ tube test positive [Figure 2]c. Subculture was done by the Dalmau plating technique [Figure 2]d on corn-meal agar to detect the presence of chlamydospores which was positive in C. albicans.
|Figure 2: (a) Culture of Candida spp. on Sabouraud's dextrose agar showing white creamy colony. (b) Culture on CHROMagar media showing growth of Candida tropicalis with blue color (upper right) and Candida parapsilosis with pale white color (left side). (c) Microphotograph of Candida albicans showing germ tube (wet mount, ×40). (d) Dalmau plating technique of Candida albicans on corn meal agar for demonstration of chlamydospore|
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The dermatophytes were differentiated on the basis of typical morphology of macroconidia on Lactophenol cotton blue preparation. Trichophyton showed few typical pencil-shaped macroconidia with abundant microconidia [Figure 3]a. Trichophyton rubrum was differentiated from Trichophyton mentagrophytes by its production of characteristic red pigment [Figure 3]b. Urease test was positive for T. mentagrophytes and negative for T. rubrum.
|Figure 3: (a) Microphotograph of Trichophyton rubrum showing pencil-shaped macroconidia (Lactophenol cotton blue preparation, ×40). (b) Culture of Trichophyton rubrum on Sabouraud's dextrose agar showing red pigmentation|
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Aspergillus fumigates was noted as macroscopically velvety green-colored colony [Figure 4]. Microscopically, it showed single layer of phialide covering upper two-third of the vesicle. Aspergillus flavus on the other hand produced velvety yellow-colored colony. Microscopically, the phialides covered three quarters of the entire surface of the vesicle.
|Figure 4: Culture of Aspergillus fumigates on Sabouraud's dextrose agar showing velvety green colony|
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The antifungal sensitivity testing of the individual fungus was done by inoculation on Mueller–Hinton agar + 2% glucose and 0.5 μg/ml methylene blue dye (GMB) medium. For standardization of the inoculum density, a barium sulfate suspension with turbidity, equivalent to a 0.5 McFarland standard or its optical equivalent, was used for the disk diffusion method. Antifungal sensitivity was done against the Candida spp. using C. albicans ATCC 10231 as control strains. Itraconazole 10 μg and fluconazole 25 μg discs were used. The recently published NCCLS breakpoint criteria have been used. Isolates were classified as susceptible if the minimum inhibitory concentration (MIC) for the isolate was ≤8 μg/ml, susceptible-dose dependent (S-DD) if the MIC was 16–32 μg/ml, and resistant if the MIC was ≥64 μg/ml. S-DD isolates were resistant at the therapeutically used dosage, but were susceptible at a higher dose.
Sensitivity with Etest strips was done to determine the MIC as was read at the point of intersection between the halo and the Etest strip. The MIC values (μg/mL) of the Etest tape were interpreted as sensitive and resistant using the NCCLS reference.
The target sample size is 15 onychomycosis patients in each treatment group. This was calculated considering mycological cure of 85% in one arm (amorolfine and fluconazole) and 40% in the fluconazole only group, with 80% power and 0.05 probability of type 1 error, for this parameter. Considering a 10% possible dropout rate, this translated to a recruitment target of approximately 17 patients per group or 34 patients overall. Mann–Whitney U-test and Wilcoxon matched pairs signed-rank test were employed for comparison of unpaired and paired nonparametric data. Friedman's analysis of variance was carried out with nonparametric data for within-group repeated measures comparisons, followed by post hoc Dunn's test. Categorical data were compared between groups by Chi-square test or Fisher's exact test, as appropriate. MedCalc version 11.6 (Mariakerke, Belgium: MedCalc Software, 2011) software was used for statistical analysis. Modified intention to treat analysis was done for effectiveness parameters with the patients coming for at least one follow-up after baseline. Missing values were dealt with the last observation carryforward strategy.
| Results|| |
The flow of study participants is given in [Figure 5]. Of 42 patients screened, 34 were randomized equally into either treatment arms. In each group, two patients were lost to first follow-up, leaving 15 analyzable in each set by the modified intention-to-treat criteria.
Our study participants were mostly middle-aged males, engaged nearly comparably in wet work and nonwet work. The duration of the disease was about 16 months in amorolfine nail lacquer + fluconazole group and 13 months in fluconazole + dummy lacquer group (P = 0.868) [Table 1].
The number of nails involved was comparable at baseline (P = 0.109) between the treatment groups. Amorolfine nail lacquer + fluconazole group showed a significant decline in the number of nails involved from the second follow-up onwards till the study ended (P < 0.001), whereas the participants treated with fluconazole + dummy lacquer did not show any significant change even at the end of 3 months of treatment (P = 0.145). Between-group comparison showed significant improvement in combination group than fluconazole only group from the 2nd follow-up onward (P = 0.004) [Table 2].
There was a significant decline in the area of nail involved in both the study groups (P < 0.001), but this decline was quicker in the combination group (1st follow-up onward) than the fluconazole only group (2nd follow-up onward). When the area of nail involved was compared between the two groups, it was found that the amorolfine nail lacquer + fluconazole group showed a significantly greater decrease than the fluconazole + dummy lacquer group, starting after 4 weeks of therapy onward [Table 3]. It was found that there was 93.3% adherence to therapy with two participants in the combination group missing one dose of fluconazole each.
|Table 3: Comparison of area of nail involved (as percentage of whole) in two treatment groups|
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Mycological cure assessed by fungal culture showed that in the fluconazole + dummy lacquer arm, 6 patients had fungal elements present compared to no patients in the amorolfine nail lacquer + fluconazole group (P = 0.012, Mann–Whitney U-test). Fungal culture at baseline showed the presence of dermatophytes (n = 15) (T. rubrum [n = 7], T. mentagrophytes [n = 5], and Epidermophyton floccosum [n = 3]) most commonly, followed by Candida (n = 11) (C. albicans [n = 8], C. parapsilosis [n = 1], and C. tropicalis [n = 1]). Aspergillus (n = 4) (Aspergillus fumigatus [n = 3], Aspergillus flavus [n = 1]) were also implicated in a few cases [Table 4].
Antifungal sensitivity for Candida (n = 11) was tested and it was found that 8 (72.7%) of the organisms were sensitive to fluconazole (MIC 1.25 ± 1.19 μg/ml) [Figure 6], 100% were sensitive to itraconazole (MIC 0.0726 ± 0.021 μg/ml) [Figure 7], and 3 (27.3%) were S-DD to fluconazole (MIC 16 μg/ml).
|Figure 6: Etest of Candida albicans with fluconazole showing minimum inhibitory concentration of 0.25 μg/ml|
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|Figure 7: Etest of C. albicans with itraconazole showing minimum inhibitory concentration of 0.064 μg/ml|
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Of the patients who were S-DD to fluconazole, two belonged to combination group and one to only fluconazole group. Of these patients with fluconazole S-DD candidial onychomycosis, combination group patients showed 55.56 ± 35.36% reduction in the area of nail involved, whereas resistant only fluconazole group patients showed no reduction in the area of nail involved.
DLQI in amorolfine nail lacquer + fluconazole group showed a significant decline (P < 0.001) from baseline (13.41 ± 5.66) to end of treatment at 12-week (8.56 ± 8.24). In the fluconazole + dummy lacquer group, changes in DLQI from baseline to the study end was not statistically significant (P = 0.712). Also, at the end of therapy, the quality of life was significantly better in combination group than fluconazole group (P < 0.001). The changes in laboratory parameters were within normal limits and no adverse reactions were noted.
| Discussion|| |
Fungal nail infections are one of the most obstinate superficial fungal infections which require long-term medications, greater time to resolve, and are yet a never-ending story. The treatment of onychomycosis has improved with the introduction of azole and allylamine antifungals. However, terbinafine and itraconazole have their own limitations of drug interactions; with liver damage and increasing age, this problem becomes increasingly relevant. It also needs to be mentioned that with long treatment, the price of terbinafine and itraconazole becomes added problem (median price of terbinafine 28.76 INR and itraconazole 36.51 INR). Fluconazole (median price 20.5 INR) is a cost-effective and safer alternative to the above-mentioned drugs.
The study population suffering from onychomycosis had an average age of 40 and mostly affected males similar to a study by Baran et al. where the average age of presentation was 46.9 ± 14.2 years and had nearly equal gender distribution.
Fluconazole and amorolfine act at sequential steps to prevent fungal ergosterol biosynthesis. Fluconazole is a highly selective inhibitor of fungal cytochrome P450-dependent enzyme lanosterol 14 α-demethylase. Thus, lanosterol is not converted to ergosterol. Amorolfine interferes with ergosterol biosynthesis at two steps: the delta 14 reduction and the delta 7–8 isomerization. Delta 14 sterol ignosterol accumulates in the cell membrane and ergosterol is depleted. This double-pronged attack has an added effect as we see in the patients treated with both the drugs. Such patients had an earlier response (after 4 weeks therapy) compared to those treated with only fluconazole (response started at 8 weeks). It is pertinent to say that the decrease in percentage area of nail involved was significantly higher in the amorolfine + fluconazole group, making the duo more effective than the singular fluconazole agent. Furthermore, the number of nails involved had a steady and quicker decrease after 8 weeks when treated with both the agents whereas those treated with only fluconazole showed no significant decrease. All the nails were declared free of fungus in all cases of amorolfine + fluconazole group; thus, a higher mycological cure was achieved. The combination group saved the participants from their embarrassing cosmetic deformity and made them better suited both at home and workplaces due to their significant improvement in quality of life. Adverse effects were not observed, thus making the combination a safe and effective one. Baran et al. explored the combination of oral terbinafine (either 6 or 12 weeks) and topical amorolfine (for 15 months) in toenail onychomycosis and had found that 44% effectiveness (both mycological and clinical cure) in terbinafine 6 weeks + amorolfine group and 72.3% effectiveness in the terbinafine 12 weeks + amorolfine group at 18 months of treatment. The study being on toenails required more time than fingernails, and the fungus was still detected at the study end. In another study by Rigopoulos et al., 85 patients treated with either itraconazole pulse therapy for 2 months with or without amorolfine nail lacquer for 6 months in candidal fingernail onychomycosis showed mycological cure 74% and 60%, respectively, with no statistically significant difference between the groups. Thus, it can be highlighted that in our study population, complete mycological cure could be achieved without using the expensive oral antifungal alternatives (terbinafine/itraconazole) by the addition of amorolfine nail lacquer along with fluconazole, both to be used only once a week and thus improving the patient compliance.
Trichophyton was the most-noted species of fungus causing onychomycosis, followed by Candida similar to the study by Thomas et al. Resistance to antifungal agents is a growing nuisance, and delayed response, no response, or recurrence might be attributed to it. Candida, a leading cause of fingernail onychomycosis, showed S-DD; thus resistant at the therapeutically used dosage of fluconazole in 30% cases but were 100% sensitive to itraconazole. Antifungal resistance is indeed a pressing problem to dermatologists, so we compared how the patients with S-DD to fluconazole fared when topical amorolfine was added to therapy. It was found that there was 55% reduction in the area of nail involved in the fluconazole-resistant patients treated with amorolfine, whereas no change was noted in the S-DD patients treated with only fluconazole.
The occurrence of S-DD among the Candida spp. also has the clinical implication and opens the scope of managing the situation by increasing the dose of fluconazole. In a pharmacokinetic study, it was found that daily dose of 400 mg achieves a serum concentration level of 10 μg/ml throughout the dosing interval. It is thus recommended that pharmacokinetic studies evaluating the dose required to achieve the high fluconazole concentration in nails (above the S-DD MIC of >16 μg/ml) has to be undertaken to formulate rational drug regime for such clinical situation.
Fungi are difficult to culture and no growth is quite common in our settings. Thus, in such resource-poor settings, treatment with the topical agent amorolfine has shown promise even in S-DD species without increasing the dose of fluconazole.
The limitation of our study was that we could not perform antifungal sensitivity in dermatophytes due to logistic limitations. We only recruited patients with fingernail onychomycosis due to operational reasons.
| Conclusion|| |
Combination of fluconazole and amorolfine is a safe and effective modality in the treatment of fingernail onychomycosis with a complete mycological cure at the end of 3 months, and the combination therapy is better than systemic therapy with fluconazole alone. Amorolfine also succeeds in clinical improvement of those cases which are S-DD to fluconazole.
Financial support and sponsorship
The study was funded by IADVL WB research grant.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]
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