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

ABSTRACT

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 SUBA^TM (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.

KEYWORDS:

• Antifungals
• resistance
• Trichophyton
• dermatophytes
• Erg1
• Erg 11
• terbinafine
• itraconazole
• tinea corporis

Article highlights

• The mechanisms responsible for treatment failure include mutations, mainly Erg1 mutations for terbinafine and Erg11 mutations for itraconazole.

• Apart from mutations, heat shock proteins, efflux pumps, protein kinases, drug detoxifications and biofilms may also play a major role in clinical failure to antifungals.

• Although minimum inhibitory concentration of itraconazole remains low, there are reports of both slow response and failure to this drug, especially with the emerging T. indotineae species.

• There is need of synergy data on the prevalent species, preferably from clinical failure cases with proven mutations, after excluding lack of compliance, steroid abuse and quality aspects of drugs specially itraconazole.

• Novel approaches in recalcitrant dermatophytoses include administration of newer formulation of itraconazole such as SUBA^TM itraconazole, use of drugs with low minimum inhibitory concentration, judicious use of combination of topical and oral antifungals based on synergy data.

• Newer therapeutic options which target resistance mechanisms such as efflux pump inhibitors, heat shock protein inhibitors and kinase inhibitors may be useful in clinical failure cases.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors substantially contributed to the conception and design of this article as well as the interpretation of relevant literature. In addition, the authors have been involved in writing the article and revising it for intellectual content.

Additional information

Funding

This paper was not funded.