An update on the myriad antifungal resistance mechanisms in dermatophytes and the place of experimental and existential therapeutic agents for Trichophyton complex implicated in tinea corporis and cruris.

INTRODUCTION: There is an epidemic emergence of increased resistance in dermatophytes with to antifungal drugs with ergosterol1 (Erg1) and Erg11 mutations to terbinafine and azoles. Apart from mutations, mechanisms that predict clinical failure include efflux pumps, cellular kinases, heat shock proteins (Hsp), and biofilms. Apart from itraconazole and SUBATM (Super-Bioavailable) itraconazole, measures that can be used in terbinafine failure include efflux-pump inhibitors, Hsp inhibitors and judicious use of antifungal drugs (topical + systemic) combinations. AREAS COVERED: A PubMed search was done for the relevant studies and reviews published in the last 22 years using keywords dermatophytes OR Trichophyton, anti-fungal, resistance, mechanism and fungal AND resistance mechanisms. Our aim was to look for literature on prevalent species and we specifically researched studies on Trichophyton genus. We have analyzed varied antifungal drug mechanisms and detailed varied experimental and approved drugs to treat recalcitrant dermatophytosis. EXPERT OPINION: Apart from administering drugs with low minimum inhibitory concentration, combinations of oral and topical antifungals (based on synergy data) and new formulations of existing drugs are useful in recalcitrant cases. There is a need for research into resistance mechanism of the existent Trichophyton strains in therapeutic failures in tinea corporis & cruris instead of data derived from laboratory strains which may not mirror clinical failures.

Treatment recalcitrant cases of tinea corporis/cruris caused by T. mentagrophytes - interdigitale complex with mutations in ERG11 ERG 3, ERG4, MDR1 MFS genes & SQLE and their potential implications.

BACKGROUND: Recalcitrant dermatophyte infections are being reported from various parts of the world due to varied causes including strain variation, steroid misuse, SQLE mutations, and variable quality of itraconazole pellet formulations. The oral drug preferred in endemic areas is itraconazole, to which MIC levels remain low, and clinical failures to itraconazole reported defy a sound scientific explanation. OBJECTIVES: The objective of the study was to conduct a proteomic and genomic analysis on isolates from therapeutically recalcitrant case with isolation of gene mutations and enzymatic abnormalities to explain azole failures. METHODS: Trichophyton mentagrophyte interdigitale complex strains were isolated from seven clinically non-responding tinea corporis/cruris patients, who had failed a sequential course of 6 weeks of terbinafine 250 mg QD and itraconazole 100 mg BID. After AFST 1 strain, KA01 with high MIC to most drugs was characterized using whole genome sequencing, comparative proteomic profiling, and total sterol quantification. RESULTS: Sterol quantification showed that the standard strain of Trichophyton mentagrophytes (MTCC-7687) had half the ergosterol content than the resistant KA01 strain. Genomic analysis revealed mutations in SQLE, ERG4, ERG11, MDR1, MFS genes, and a novel ERG3 mutation. Proteomic analysis established the aberrant expression of acetyl Co-A transferase in the resistant strain and upregulation of thioredoxin reductase and peroxiredoxin. CONCLUSION: Our findings demonstrate possible reasons for multidrug resistance in the prevalent strain with mutations in genes that predict terbinafine (SQLE) and azole actions (ERG4, ERG11, ERG3) apart from efflux pumps (MDR1, MFS) that can explain multidrug clinical failures.

Complete cure of Fusarium solani sp. complex onychomycosis with Qs NdYAG treatment.

The incidence of non dermatophytic mould (NDM) onychomycosis (OM) has been steadily increasing Fusarium spp is the most common cause of NDM OM in most geographical locations. Fusarium spp and other NDMs are largely resistant to commonly used anti-fungals. The successful use of laser and light based devices has been demonstrated in dermatophytic OM, but there is no previous report of their successful use in any NDM OM. We describe a patient with OM caused by Fusarium solani spp, who was clinically (with a normal appearing nail) and mycologically (with negative microscopy and culture on repeated samples) cured of her infection following treatment with 2 sessions of Qs NdYAG (532nm and 1064nm) given 1 month apart.