ACKNOWLEDGEMENTS: Medical writing support was provided by Prescott Medical Communications Group (Chicago, IL) with financial support from Ortho Dermatologics; Ortho Dermatologics is a division of Bausch Health US, LLC • Presented at Winter Clinical Dermatology Conference 2023 • January 13-18, 2023 • Waimea, HI Efinaconazole in the Age of Antifungal Resistance Ahmed Gamal,1 Mohammed Elshaer,1,2 Lisa Long,1 Thomas S. McCormick,1 Boni Elewski,3 Mahmoud A. Ghannoum1,4 1Case Western Reserve University, Cleveland, OH; 2Mansoura Faculty of Medicine, Mansoura, Egypt; 3University of Birmingham, AL; 4University Hospitals Cleveland Medical Center, Cleveland, OH.*Bausch Health US, LLC is an affiliate of Bausch Health Companies Inc. BACKGROUND � The global rise and spread of antifungal resistance is complicating the treatment of onychomycosis, a fungal infection of the toenail bed or plate � Causative dermatophyte species resistant to oral antifungals like terbinafine are being increasingly detected1,2 � Further, resistant yeast and mold species are now categorized by the World Health Organization as fungal pathogens that represent a great threat to public health3 � Accordingly, patients in the US are presenting with onychomycosis resistant to terbinafine or second-line systemic therapies like oral fluconazole or itraconazole4 � It is crucial to find alternative approaches to combat this clinical resistance, including implementing antifungal stewardships programs and identifying antifungals that are effective against both susceptible and resistant fungal strains OBJECTIVE � The goal of this study was to evaluate the activity of oral and topical antifungals against susceptible and resistant clinical isolates of dermatophytes, yeasts, and molds METHODS � Antifungal activity of efinaconazole was compared with terbinafine, itraconazole, and fluconazole using in vitro assays evaluating minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) against susceptible and resistant strains � MIC is the lowest concentration of an antifungal that inhibits fungal growth (threshold for inhibition varies depending upon fungus being tested); MIC50 is the lowest concentration that inhibits growth in 50% of the fungal isolates tested • MIC testing was performed according to the Clinical and Laboratory Standard Institute (CLSI) microdilution methods for yeasts5 and for dermatophytes and non-dermatophyte molds6 � MFC determines if a test compound is fungicidal (≥99.9% reduction of the fungus) or fungistatic � Lower MIC and MFC values are more favorable, as less drug is required for antifungal activity � Clinical isolates tested due to suspicion of antifungal resistance included: • Dermatophytes (Trichophyton mentagrophytes [n=16], T. rubrum [n=43], T. tonsurans [n=18], and T. violaceum [n=4]) • Yeasts (Candida albicans [n=55] and C. auris [n=30]) • Molds (Fusarium sp., Scedosporium sp., and Scopulariopsis sp. [n=15 each]) RESULTS � Efinaconazole showed superior potent activity against a broad panel of susceptible and resistant dermatophyte, Candida, and mold isolates (Figures 1–3) � Although none of the tested compounds showed fungicidal activity against all tested isolates, efinaconazole demonstrated more fungicidal activity against T. rubrum isolates compared to other antifungals (data not shown) FIGURE 3. Antifungal Ac tivity Against Molds 100 10 1 0.010.1 Drug concentration (µg/mL) on logarithmic scale Fluconazole (2 – >64) Terbina�ne (0.5 – >64) Itraconazole (1 – >64) E�naconazole (0.016 – 2) More potent antifungal activity All Mold Isolatesa (n=45) E�naconazole was the most active compound against different types of molds, including those with high itraconazole and terbina�ne MICs aScedosporium, Fusarium spp., Scopulariopsis. Bar graphs indicate MIC ranges for all isolates tested; range values indicated below drug name. CONCLUSIONS � Efinaconazole demonstrated superior in vitro activity compared to fluconazole, itraconazole, and terbinafine against a broad range of dermatophytes and non-dermatophytes commonly implicated in onychomycosis � Efinaconazole also demonstrated potent antifungal activity against isolates resistant to terbinafine and/or itraconazole, suggesting efinaconazole may be an efficacious treatment for resistant organisms REFERENCES 1. Hiruma J, et al. J Dermatol. 2021;48(4):564-567. 2. Noguchi H, et al. J Dermatol. 2019;46(12):e446-e447. 3. World Health Organization. WHO releases first-ever list of health-threatening fungi. Accessed November 29, 2022. https://www.who.int/news/item/25-10- 2022-who-releases-first-ever-list-of-health- threatening-fungi. 4. Gu D, et al. JAAD Case Rep. 2020;6(11):1153-1155. 5. Clinical and Laboratory Standards Institute. 2017. Document M27Ed4E. 6. Clinical and Laboratory Standards Institute. 2017. Document M38Ed3E. AUTHOR DISCLOSURES Boni Elewski has provided clinical research support (research funding to University) for AbbVie, Anaptys-Bio, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Incyte, LEO Pharma, Lilly, Merck, Menlo, Novartis, Pfizer, Regeneron, Sun Pharma, Ortho Dermatologics, and Vanda; and as consultant (received honorarium) from Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, LEO Pharma, Lilly, Menlo, Novartis, Pfizer, Sun Pharma, Ortho Dermatologics, and Verrica. Mahmoud Ghannoum has acted as a consultant or received contracts from Scynexis, Inc, Bausch & Lomb, Pfizer, and Mycovia. The remaining authors have nothing to disclose. FIGURE 1. Antifungal Ac tivity Against Dermatophy tes E�naconazole demonstrated the most potent antifungal activity against 81 dermatophyte isolates, including 27 resistant isolates with elevated MICs against terbina�ne 100 10 1 0.1 0.0010.01 Drug concentration (µg/mL) on logarithmic scale MIC 50 = 1 Fluconazole(≤0.125 – >64) MIC 50 = 0.03 Terbina�ne(≤0.001 – >64) MIC 50 = 0.03 Itraconazole(≤0.016 – 1) MIC 50 = 0.002 E�naconazole(≤0.001 – 0.25) More potent antifungal activity All Dermatophyte Isolates (n=81) 100 10 1 0.1 0.0010.01 Drug concentration (µg/mL) on logarithmic scale MIC 50 = 0.5 Fluconazole(≤0.125 – 32) MIC 50 = 4 Terbina�ne(0.5 – >64) MIC 50 = 0.03 Itraconazole(≤0.016 – 0.5) MIC 50 = 0.002 E�naconazole(≤0.001 – 0.25) More potent antifungal activity Resistant Dermatophyte Isolatesa (n=27) aResistant dermatophytes defined as isolates that showed elevated MIC values against terbinafine. Bar graphs indicate MIC ranges for all isolates tested; range values indicated below drug name. Diamonds indicate MIC50, defined as lowest concentration of antifungal that inhibits growth in 50% of the isolates tested. FIGURE 2. Antifungal Ac tivity Against Candida 0.001100 10 1 0.1 0.00010.01 Drug concentration (µg/mL) on logarithmic scale MIC 50 = 1 Fluconazole(≤0.125 – >64) MIC 50 = 2 Terbina�ne(≤0.125 – >64) MIC 50 = 0.25 Itraconazole(≤0.03 – >64) MIC 50 = 0.016 E�naconazole(≤0.00024 – 32) More potent antifungal activity 100 10 1 0.1 0.0010.01 Drug concentration (µg/mL) on logarithmic scale Terbina�ne (16 – >64) Itraconazole (1 – >64) E�naconazole (0.008 – 32) More potent antifungal activity All Isolates (n=85)Candida Resistant Isolatesa (n=11)Candida E�naconazole demonstrated the most potent antifungal activity against 85 isolates, including 11 isolates with high itraconazole and/or terbina�ne MICsCandida aResistant Candida: four C. albicans isolates with elevated MICs against terbinafine, four isolates (C. albicans and C. auris) with elevated MICs against itraconazole, and three C. albicans isolates with elevated MICs against both terbinafine and itraconazole. Bar graphs indicate MIC ranges for all isolates tested; range values indicated below drug name. Diamonds indicate MIC50, defined as lowest concentration of antifungal that inhibits growth in 50% of the isolates tested.