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Background: Onychomycoses are difficult-to-treat fungal infections with high relapse rates. Combining oral and topical antifungal drugs is associated with higher success rates. Additive or synergistic modes of action are expected to enhance treatment success rates., Objectives: Investigation of the combined effects of antifungal drugs in vitro with different modes of action and application on clinical isolates from mycotic nails., Methods: Isolates of Trichophyton rubrum, Trichophyton interdigitale and Scopulariopsis brevicaulis were collected from infected toenail specimens of patients with onychomycosis. Susceptibility testing was performed in 96-well polystyrene plates using a standard stepwise microdilution protocol. Additive or synergistic activity at varying concentrations was investigated by the checkerboard method., Results: Combining terbinafine with amorolfine tended to be more effective than terbinafine in conjunction with ciclopirox. In most combinations, additive effects were observed. Synergy was detected in combinations with involving amorolfine in S. brevicaulis. These additive and synergistic interactions indicate that combined therapy with topical amorolfine and oral terbinafine is justified. Sublimation of amorolfine (and terbinafine) may enhance the penetration in and through the nail plate, and support treatment efficacy., Conclusions: These in vitro results support the notion that combining oral terbinafine and topical amorolfine is beneficial to patients with onychomycosis, particularly if the pathogen is a non-dermatophyte fungus such as S. brevicaulis., (© 2024 The Authors. Mycoses published by Wiley-VCH GmbH.)

Background: Onychomycosis affects up to 50% of patients in the older population., Objectives: This study aimed to explore heat sensitivity of Trichophyton rubrum and Trichophyton interdigitale as pathogens of onychomycosis., Materials & Methods: The fungi were heated in sterile saline solution up to 100°C for five or 10 minutes with or without additional previous treatment with 1% ciclopirox solution or chitinase and 1,3 -galactidase or for 45 minutes at 40°C or 60°C with washing powder. Subsequently, the fungi were cultured and regrowth was assessed after one week., Results: After heating T. rubrum for five minutes at 60°C, growth was completely inhibited. After heating T. interdigitale for five minutes at 60°C, all of the samples regrew, and at 95°C, none of the samples regrew. No difference between five and 10-minute heating was observed. Previous incubation with 1% ciclopirox solution for 24 hours inhibited the growth of T. rubrum completely. T. interdigitale was still able to regrow to 100% after five minutes at 40°C, to 33% after 60°C, and to 22% after 80°C. Incubation for 45 minutes with washing powder solution at 40°C or 60°C did not lead to significant growth reduction of T. rubrum or interdigitale. Two hours incubation with -1,3-glucanase and chitinase prior to five minutes of heating to 60°C and 80°C reduced the heat resistance of T. interdigitale; growth was inhibited in 56% and 100% of the samples, respectively., Conclusion: The heat resistance of T. rubrum and interdigitale should be considered using non-medical thermal treatment.

Bacterial nanocellulose has been widely investigated for wound healing applications, mainly due to its moisturizing capabilities and biocompatibility. Even though the topical therapy of nail diseases could benefit from these properties, this application has not yet been investigated. Therefore, actively hydrating nail patches based on bacterial nanocellulose were developed to improve the delivery of ciclopirox olamine and Boswellia serrata extract through the nail plate. The nanocellulose matrix was used to enable the application of hydration enhancing solutions based on glycerol and urea as a mechanically stable patch. While the favorable mechanical characteristics of the material remained unchanged, an increase of the incorporated glycerol concentration enhanced the transparency and wetting capacity of the patches. A biphasic drug release from the patches could be observed for drug and extract with a faster release for the hydrophilic ciclopirox olamine. High glycerol concentrations correlated with increased cumulative release and permeation through keratin films for drug and extract, demonstrating the hydration driven permeation enhancement. Patches containing ciclopirox olamine showed strong antimycotic effects against relevant pathogens for onychomycosis. The present finding proposed the combination of bacterial nanocellulose with glycerol, urea and different drug as a promising platform for the local treatment of nail diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Onychomycosis is a nail infection caused by Trichophyton interdigitale and other fungi, which can be treated with topical amorolfine (AMR) and ciclopirox olamine (CPX). Although these drugs are widely used, little is known about the role of reactive oxygen (ROS) and nitrogen (RNS) in their mechanism of action. To better understand the effects of AMR and CPX in dermatophytes, we evaluated whether they act through the production of ROS and peroxynitrite (PRN). We tested a set of strains, all susceptible to AMR and CPX, and these antifungals significantly reduced T. interdigitale viability within 24 h. This effect occurred concomitantly with reduced ergosterol, increased production of ROS and PRN, and consequently increased lipid peroxidation. Together, these mechanisms lead to cell damage and fungal death. These fungicidal effects were abolished when PRN and superoxide scavengers were used in the assays, demonstrating the role of these species in the mechanism of action. We also studied the antioxidant system when T. interdigitale was exposed to AMR and CPX. Interestingly, superoxide dismutase and catalase inhibition lead to altered ROS and PRN production, lipid peroxidation, and ergosterol levels. In fact, the combination of AMR or CPX with a superoxide dismutase inhibitor was antagonistic. Together, these data demonstrate the importance of ROS and PRN in the antifungal action of AMR and CPX against the evaluated T. interdigitale strains., Lay Summary: Onychomycosis is a nail infection, which can be treated with amorolfine and ciclopirox olamine. Here we demonstrate that these drugs exhibit antifungal activity also through the production of oxidative and nitrosative radicals., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) is a mass spectrometry-based technique, which can be applied for compound-specific imaging of pharmaceuticals in tissues samples. MALDI-MSI technology is widely used to visualise penetration and distribution profile through different tissues but has never been used with nail tissue., Objectives: This study used MALDI-MSI technology to visualise distribution profile and penetration into ex vivo human mycosis-infected toenails of three antifungal active ingredients amorolfine, ciclopirox and naftifine contained in topical onychomycosis nail treatment preparations, marketed as Loceryl ® , Ciclopoli ® and Exoderil ® ., Methods: Three mycosis-infected toenails were used for each treatment condition. Six and twenty-four hours after one single topical application of antifungal drugs, excess of formulation was removed, nails were cryo-sectioned at a thickness of 20 μm, and MALDI matrix was deposited on each nail slice. Penetration and distribution profile of amorolfine, ciclopirox and naftifine in the nails were analysed by MALDI-MSI., Results: All antifungal actives have been visualised in the nail by MALDI-MSI. Ciclopirox and naftifine molecules showed a highly localised distribution in the uppermost layer of the nail plate. In comparison, amorolfine diffuses through the nail plate to the deep layers already 6 hours after application and keeps diffusing towards the lowest nail layers within 24 hours., Conclusions: This study shows for the first-time distribution and penetration of certain antifungal actives into human nails using MALDI-MSI analysis. The results showed a more homogeneous distribution of amorolfine to nail and a better penetration through the infected nails than ciclopirox and naftifine., (© 2020 Blackwell Verlag GmbH.)