ravuconazole and Dermatomycoses

Ravuconazole (RVCZ) is a new human anti-fungal azole drug available in Japan since 2018 and is a broad-spectrum agent that exhibits excellent activity against dermatophytes. In the present study, the in vitro RVCZ susceptibility of clinical isolates of anthropophilic dermatophytes, including Trichophyton interdigitale strains with either low susceptibility to itraconazole (ITCZ) or resistance to terbinafine (TEBR), was investigated using the Clinical & Laboratory Standards Institute M38-A2 test. The MICs of RCVZ for 20 clinical isolates of T. interdigitale were < 0.03125-0.125 mg/L; for 4 clinical isolates of T. rubrum, < 0.03125-0.0625 mg/L; and for 20 clinical isolates of T. tonsurans, < 0.03125 mg/L. Similarly, the MICs of RCVZ for the T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR were also < 0.03125 mg/L. To our knowledge, this is first study to investigate the in vitro RVCZ susceptibility of T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR. Our results indicated that RVCZ was the most effective drug against these strains.

Topics: Antifungal Agents; Arthrodermataceae; Dermatomycoses; Drug Resistance, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Terbinafine; Thiazoles; Triazoles

Malassezia pachydermatis, a lipophilic and aerobic yeast, is a causative agent of Malassezia dermatitis, a common skin mycosis in dogs and cats. This fungus is also responsible for zoonotic fungal infections in human neonates. Ravuconazole (RVZ) is an antifungal azole compound and the active metabolite of fosravuconazole, which was approved for use in humans in Japan in 2018. In the present study, in vitro RVZ susceptibility and multi-azole resistance of 13 clinical M. pachydermatis strains was investigated using the modified Clinical and Laboratory Standards Institute M27-A3 test. The minimum inhibitory concentrations (MICs) for the 13 isolates ranged from 0.094 to >32 mg/L for itraconazole (ITZ) and from 0.5 to >32 mg/l for RVZ. Similarly, MICs for ITZ- or RVZ-resistant strains (MICs >32 mg/l) were also >32 mg/l for clotrimazole (CTZ), >32 mg/l for miconazole (MCZ), and 0.25 to >32 mg/L for voriconazole (VRZ). BLAST analysis using the NCBI database showed that ERG11 cDNA of the RVZ-resistant strain encoded Gly at codon 461 and Asp in cytochrome p450 encoded by M. pachydermatis ERG11 mRNA. This work is the first report to describe that an RVZ-resistant M. pachydermatis strain contains ERG11 mutations. The affinity of the protein encoded by ERG11 for RVZ may differ from that of ITZ. Therefore, RVZ has considerable therapeutic potential for treating ITZ-resistant canine Malassezia dermatitis. However, RVZ-resistant strains already exist in canine Malassezia dermatitis in Japan.

Topics: Animals; Antifungal Agents; Azoles; Dermatomycoses; Dog Diseases; Dogs; Drug Resistance, Multiple, Fungal; Itraconazole; Japan; Malassezia; Microbial Sensitivity Tests; Thiazoles; Triazoles

The in vitro activity of ravuconazole (RVCZ) was compared with those of itraconazole (ITCZ) and terbinafine (TBF) against 73 dermatophyte isolates and 18 Candida spp. isolates recovered from patients with dermatomycosis at 4 dermatological clinics in Japan in 2011. The dermatophyte isolates consisted of Trichophyton rubrum (n=51), Trichophyton mentagrophytes (n=20 : these strains were not identified by molecular phylogenetic analysis.), Trichophyton tonsurans (n=1), and Microsporum canis (n=1). The Candida spp. isolates comprised C. albicans (n=11), C. parapsilosis (n=5), C. guilliermondii (n=1), and C. pseudohaemulonii (n=1). RVCZ was highly active against all dermatophytes and all Candida spp. : the geometric mean (GM) MICs for T. rubrum and T. mentagrophytes were 0.035 μg/mL and MICs for T. tonsurans and M. canis were ≤ 0.03 μg/mL, and GM MICs for C. albicans and C. parapsilosis were ≤ 0.03 μg/mL and MICs for C. guilliermondii and C. pseudohaemulonii were 0.25 and ≤ 0.03 μg/mL, respectively. Compared to RVCZ, ITCZ showed similar anti-dermatophytic and anti-Candida activities, while TBF had a slightly higher anti-dermatophytic but a markedly lower anti-Candida activity. These results suggest that RVCZ is a potential candidate systemic antifungal therapy against onychomycosis and other dermatomycoses that are refractory to topical antifungal therapy.

Topics: Antifungal Agents; Arthrodermataceae; Candida; Dermatomycoses; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Humans; Itraconazole; Naphthalenes; Terbinafine; Thiazoles; Triazoles