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

Abstract

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...

<p>Emergence of Terbinafine Resistant <em>Trichophyton mentagrophytes</em> in Iran, Harboring Mutations in the Squalene Epoxidase (<em>SQLE</em>) Gene</p>

“…The antifungal susceptibility profile of Iranian TMTISG isolates, described in our results (Table 1), was comparable to that ones from other Iranian and foreign studies. 12,[27][28][29][30] The MIC values of EFN against TMTISG isolates from Japan, Canada, US and Iran in three studies all in all ranged from 0.001 to 0.03 µg/mL. [27][28][29] They did not differ significantly from the MIC values for EFN in the current study (MICs = 0.001-0.125 µg/mL).…”

Efficacy and safety of luliconazole 5% nail solution for the treatment of onychomycosis: A multicenter, double‐blind, randomized phase III study

“…While the present study provides only data from Japanese patients, similar efficacy results are expected in other races and regions, as luliconazole exerts high antifungal activities against various strains of fungi. 35 Luliconazole also showed a favorable safety profile. There were a few ADR but all were associated with local symptoms and improved after discontinuation of luliconazole.…”

“…While the present study provides only data from Japanese patients, similar efficacy results are expected in other races and regions, as luliconazole exerts high antifungal activities against various strains of fungi …”

Potent Activities of Novel Imidazoles Lanoconazole and Luliconazole against a Collection of Azole-Resistant and -Susceptible Aspergillus fumigatus Strains

“…Luliconazole affects ergosterol biosynthesis by inhibiting the azole target protein lanosterol 14␣-demethylase (cyp51A), which is the key enzyme that catalyzes the oxidative removal of the 14␣-methyl group of lanosterol to give 14-15-desaturated intermediates in ergosterol biosynthesis (9). Recently, in vitro antifungal susceptibility testing of lanoconazole and luliconazole demonstrated potent efficacy against Trichophyton rubrum and Epidermophyton floccosum (9)(10)(11)(12)(13)(14). In addition, animal studies and small human series suggested that luliconazole and lanoconazole are effective in treating dermatophytosis and onychomycosis (15,16).…”