In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes M. Ghannoum, N. Isham, L. Long Center for Medical Mycology, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, Ohio, USA The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interac- tions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight en- hances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n  400) and the minimum fungicidal con- centration (MFC) (n  300). Additionally, we examined the potential for resistance development in dermatophytes (n  4) fol- lowing repeated exposure to ME1111. Our data show that the MIC 90 of ME1111 against dermatophyte strains was 0.25 g/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 g/ml, respectively). ME1111 was fun- gicidal at clinically achievable concentrations against dermatophytes, and its MFC 90 s against Trichophyton rubrum and Tricho- phyton mentagrophytes were 8 g/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes. A mong superficial fungal infections, by far the most difficult to cure is toenail onychomycosis, which is responsible for 50% of all nail disease (1). Onychomycosis, a fungal nail infection af- fecting up to 13% of the general population (2–8) and 25% of the geriatric and diabetic population (7, 9, 10), is more than just a cosmetic problem. More importantly, onychomycosis has been reported to cause chronic pain associated with prolonged standing or walking and acute pain from footwear and cutting of the nails (11–13). The greatest predisposing risk factor for developing onycho- mycosis is advanced age, as the risk is reported to be 18.2% in patients 60 to 79 years of age compared to 0.7% in patients younger than 19 years of age. Further, men are up to 3 times more likely to have onychomycosis than women, though the reasons for this gender difference are not clear (5, 14). Other risk factors in- clude diabetes and conditions contributing to poor peripheral cir- culation (15). In fact, onychomycosis may represent an important predictor for the development of diabetic foot syndrome and foot ulcers (16). Patients who are immunosuppressed, such as those with HIV infection and those undergoing cancer therapy, are also predisposed to fungal nail infection (17). Several nonclinical risk factors also affect a person’s chance of developing fungal nail infections. For example, toenail onycho- mycosis is not prevalent in tropical climates, presumably because people in those areas are not in the habit of wearing occlusive footwear that creates a warm, moist environment for the prolifer- ation of fungi. Further, the spread of foot infections, including tinea pedis (athlete’s foot), may occur in places such as shower stalls, bathrooms, or locker rooms, where floor surfaces often are wet and people are barefoot (18). Nail trauma will also increase the risk of fungal infection of the affected nail, especially in the geri- atric population (5, 17). The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these drugs may have side effects such as liver damage or drug interactions, which are particularly relevant in the elderly population (19). Un- fortunately, currently available topical agents such as ciclopirox 8% and amorolfine 5% have low efficacy (approximately 5 to 12%) (20, 21). This low efficacy can be attributed mainly to the inability of the drug to penetrate through the nail plate to the nail bed, where the infection resides (22). Additionally, thickened nails, extensive involvement of the entire nail, lateral disease, and yellow spikes (hyperkeratotic bands extending to the nail matrix) contribute to a poor response to topical treatment (17). Thus, there remains a need for new topical agents that are effective against onychomycosis. ME1111 is a novel antifungal discovered by Meiji Seika Pharma Co., Ltd. (Tokyo, Japan), and its small molecular mass (202.25 g/mol) enhances its ability to penetrate the nail plate (Fig. 1). The investigational drug is currently under- going clinical evaluation. In this study, we determined the anti- fungal activity of ME1111 against dermatophyte species known to cause onychomycosis, as measured by MIC and minimum fungi- cidal concentration (MFC). Additionally, we examined the poten- tial for resistance development in dermatophytes following re- peated exposure to ME1111. Received 24 April 2015 Returned for modification 21 May 2015 Accepted 4 June 2015 Accepted manuscript posted online 8 June 2015 Citation Ghannoum M, Isham N, Long L. 2015. In vitro antifungal activity of ME1111, a new topical agent for onychomycosis, against clinical isolates of dermatophytes. Antimicrob Agents Chemother 59:5154 –5158. doi:10.1128/AAC.00992-15. Address correspondence to M. Ghannoum, mahmoud.ghannoum@case.edu. Copyright © 2015, American Society for Microbiology. All Rights Reserved. doi:10.1128/AAC.00992-15 5154 aac.asm.org September 2015 Volume 59 Number 9 Antimicrobial Agents and Chemotherapy on October 2, 2017 by guest http://aac.asm.org/ Downloaded from