Comparison of
            <i>In Vitro</i>
            Antifungal Activities of Efinaconazole and Currently Available Antifungal Agents against a Variety of Pathogenic Fungi Associated with Onychomycosis

Self Cite

The mechanism of action of efinaconazole, a new triazole antifungal, was investigated with Trichophyton mentagrophytes and Candida albicans. Efinaconazole dose-dependently decreased ergosterol production and accumulated 4,4-dimethylsterols and 4␣-methylsterols at concentrations below its MICs. Efinaconazole induced morphological and ultrastructural changes in T. mentagrophytes hyphae that became more prominent with increasing drug concentrations. In conclusion, the primary mechanism of action of efinaconazole is blockage of ergosterol biosynthesis, presumably through sterol 14␣-demethylase inhibition, leading to secondary degenerative changes. Ergosterol is an important structural component of fungal cell membranes, maintaining membrane fluidity and a permeability barrier, and is essential for fungal cell viability (1-3). Several classes of antifungal drugs target ergosterol biosynthesis. Among these, triazole antifungals (e.g., itraconazole) and imidazole antifungals (e.g., clotrimazole and miconazole) inhibit sterol 14␣-demethylase (14-DM) in the ergosterol biosynthesis pathway (4). The consequent ergosterol depletion affects cell membrane integrity and function and is believed to inhibit fungal cell growth and affect morphology.Efinaconazole, a novel triazole antifungal drug currently under development as a topical treatment for onychomycosis, has demonstrated efficacy in patients with toenail onychomycosis in two phase 3 clinical trials (5). Onychomycosis and other superficial mycoses are caused mainly by dermatophytes (e.g., Trichophyton rubrum and Trichophyton mentagrophytes) and yeast (e.g., Candida albicans). Efinaconazole possesses similar or higher antifungal activity against T. rubrum and T. mentagrophytes (MIC range, 0.00098 to 0.031 g/ml) and a broader spectrum of activity than those of currently marketed antifungals used in onychomycosis (6). We investigated the effects of efinaconazole on fungal ergosterol biosynthesis and dermatophyte hyphal morphology.In the present study, T. mentagrophytes strain SM-110 and C. albicans strain ATCC 10231 were used. The MICs of efinaconazole (Kaken Pharmaceutical), itraconazole, and clotrimazole (SigmaAldrich) were determined by the broth microdilution method using morpholinepropanesulfonic acid (MOPS)-buffered RPMI 1640, as described in CLSI documents M38-A2 (7) and M27-A3 (8), using visual endpoint readings of 80% growth inhibition at 4 days and 50% growth inhibition at 48 h, respectively. Efinaconazole was 4-fold more active than itraconazole against T. mentagrophytes SM-110 (MICs of 0.0039 and 0.016 g/ml, respectively). Similarly, efinaconazole was 8-fold more active than clotrimazole against C. albicans ATCC 10231 (MICs of 0.00098 and 0.0078 g/ml, respectively). The two strains showed typical susceptibilities to the antifungals tested, consistent with previous findings for these species (6, 9).Ergosterol biosynthesis assays were conducted by modifying the methods of Vanden Bossche et al. (10) and Ryder et al. (11). T. mentagrophytes (2 ϫ 10 8 microconidia/ml...

supporting

confidence: 90%

mentioning

confidence: 99%

Mechanism of Action of Efinaconazole, a Novel Triazole Antifungal Agent

Tatsumi

Nagashima

Shibanushi

et al. 2013

Self Cite

“…One limitation of this study is that we did not measure the in vitro activity of other azoles against these isolates. However, the luliconazole MIC range, MIC 50 and MIC 90 values, and GM MICs that were measured in the current study compared favorably those reported in the literature for other azoles against dermatophytes, including itraconazole, voriconazole, posaconazole, ketoconazole, and the investigational agents efinaconazole and ravuconazole (Table 3) (15)(16)(17)(18)(19)(20). Although direct in vitro comparisons with newer azoles are warranted, none of these other azoles, except for itraconazole, currently have an FDA-approved indication for the treatment of onychomycosis.…”

supporting

confidence: 71%

Luliconazole Demonstrates Potent In Vitro Activity against Dermatophytes Recovered from Patients with Onychomycosis

Wiederhold

Fothergill

McCarthy

et al. 2014

The in vitro activities of luliconazole, amorolfine, ciclopirox, and terbinafine were determined against 320 dermatophyte isolates from large toenails of onychomycosis patients enrolled into an ongoing phase 2b/3 clinical study. The geometric mean MIC for luliconazole was 0.00022 g/ml against all isolates, compared to 0.0194 to 0.3107 g/ml for the three other agents. The in vitro potency of luliconazole was maintained regardless of the dermatophyte species.O nychomycosis (tinea unguium) is a fungal infection of the nail bed and or plate and is associated with significant morbidity (1). Besides causing cosmetic concerns, this mycosis can result in pain or discomfort, acute bacterial cellulitis associated with spread of infection to the skin, and social stigma (2, 3). The prevalence of onychomycosis is estimated to be between 2 and 14%, with a rate of 13.8% reported in North America (1, 4). Risk factors for infection include increasing age, male gender, dystrophic nails, tinea pedis, and poor peripheral circulation (1, 3, 4). These infections are caused primarily by dermatophytes, including Trichophyton rubrum and T. mentagrophytes, and to a lesser extent by other dermatophytes (e.g., Epidermophyton floccosum), Candida species, and nondermatophytic molds (e.g., Acremonium, Fusarium, and Scopulariopsis species) (5, 6). Luliconazole is a novel imidazole currently under development. Pharmacokinetic and safety results from phase 1 studies in patients with onychomycosis have demonstrated high concentrations of luliconazole within the nail plates of the great toe and have shown that this agent is well tolerated when administered as a 10% solution (7). In vitro studies with a limited number of isolates have also reported potent activity of this agent against dermatophytes and other causative agents of dermatophytosis, including onychomycosis (8-10). Results from animal models and small clinical studies have also suggested in vivo efficacy against dermatophytosis (11-13). Our objective was to measure the in vitro activity of luliconazole against dermatophytes isolated at screening from toenails in an ongoing phase 2b/3 study of patients with mild to moderate toenail onychomycosis (www.clinicaltrials.gov, identifier NCT01431820). In addition, the in vitro activities of amorolfine, ciclopirox, and terbinafine, three products approved and most often used for treatment of onychomycosis in the United States and the European Union, were also determined.Three hundred twenty dermatophytes obtained from patients with confirmed toenail onychomycosis (positive KOH and culture and clinical diagnosis) during screening were used in this study. This included 308 Trichophyton rubrum and 10 T. mentagrophytes isolates and one each of Trichophyton tonsurans and Epidermophyton floccosum. All isolates were clinical strains that had been freshly subcultured and not previously frozen. Stock solutions of amorolfine, ciclopirox, terbinafine, and luliconazole were prepared in dimethyl sulfoxide (DMSO) and further diluted in RPMI 1640 buffered to a...

“…For many years, griseofulvin was the only approved systemic antidermatophytic agent (4). However, nowadays, many potent antifungal agents are available for the treatment of dermatophytosis, such as allylamines and triazoles, which have more potent activity and fewer side effects (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The expansion of information on in vitro susceptibility testing of dermatophytes to new antifungal agents will help in the selection and development of antifungal drug regimens.…”

mentioning

confidence: 99%

Comparison of the In Vitro Activities of Newer Triazoles and Established Antifungal Agents against Trichophyton rubrum

Deng

Zhang

Seyedmousavi

et al. 2015

D ermatophytosis caused byTrichophyton rubrum is the most common cutaneous fungal infection worldwide (1), which represents the cause of between 80% and 90% of all chronic and recurrent infections (2). These infections establish an important public health problem because of the prolonged treatment required for the disease, because of the frequent recurrence of infection, and because they are generally considered difficult to manage (3). Reliable in vitro susceptibility testing would therefore be useful for selecting the most suitable antifungal treatment. For many years, griseofulvin was the only approved systemic antidermatophytic agent (4). However, nowadays, many potent antifungal agents are available for the treatment of dermatophytosis, such as allylamines and triazoles, which have more potent activity and fewer side effects (5-19). The expansion of information on in vitro susceptibility testing of dermatophytes to new antifungal agents will help in the selection and development of antifungal drug regimens.The aim of the current study was to compare in vitro the activities of three newer triazoles, voriconazole, posaconazole, and isavuconazole, and four established antifungal agents against T. rubrum infection. One hundred eleven clinical isolates of T. rubrum were collected from seven dermatology clinics in Shanghai, China. Morphological identifications were confirmed by sequence-based analysis of the internal transcribed spacer of the rRNA gene region. The in vitro activities of seven antifungal agents were determined according to the CLSI reference guideline M38-A2 (20), with minor modifications. Two reference strains, Trichophyton mentagrophytes (strain ATCC MYA-4439) and Candida parapsilosis (strain ATCC 22019), were included as quality controls. Student's t test with the statistical SPSS package (version 9.0) was used, and P values of Ͻ0.05 were considered statistically significant. Table 1 lists the MIC ranges, geometric mean (GM) MICs, MIC 50 s, and MIC 90 s of seven antifungal agents against 111 T. rubrum strains. Terbinafine, voriconazole, posaconazole, isavuconazole, itraconazole, and griseofulvin had low MICs against all tested strains, whereas fluconazole did not show inhibitory effects. Similar results have been achieved in other studies (Table 2); however, limited data are available for the newer triazoles isavuconazole and posaconazole.Terbinafine was one of the most effective antifungal agents against T. rubrum among the 7 fungal agents tested, and our findings confirm those of previous studies (5-19) ( Table 2). We compared the in vitro activities of the 3 newer triazoles isavuconazole, posaconazole, and voriconazole with that of itraconazole. Three newer triazoles offered good in vitro activity against T. rubrum (Table 1). All isolates were far more susceptible to the 3 newer triazoles than to itraconazole (Table 1) and comparable to those reported by other studies (7,9,10,14,17,18).Isavuconazole is a novel broad-spectrum triazole agent and has the same mechanism of action as the other tr...