Alarming India‐wide phenomenon of antifungal resistance in dermatophytes: A multicentre study

Abstract

Background An alarming increase in recalcitrant dermatophytosis has been witnessed in India over the past decade. Drug resistance may play a major role in this scenario. Objectives The aim of the present study was to determine the prevalence of in vitro resistance to terbinafine, itraconazole and voriconazole in dermatophytes, and to identify underlying mutations in the fungal squalene epoxidase (SQLE) gene. Patients/Methods We analysed skin samples from 402 patients originating from eight locations in India. Fungi were identified by microbiological and molecular methods, tested for antifungal susceptibility (terbinafine, itraconazole, voriconazole), and investigated for missense mutations in SQLE. Results Trichophyton (T.) mentagrophytes internal transcribed spacer (ITS) Type VIII was found in 314 (78%) samples. Eighteen (5%) samples harboured species identified up to the T interdigitale/mentagrophytes complex, and T rubrum was detected in 19 (5%) samples. 71% of isolates were resistant to terbinafine. The amino acid substitution Phe397Leu in the squalene epoxidase of resistant T mentagrophytes was highly prevalent (91%). Two novel substitutions in resistant Trichophyton strains, Ser395Pro and Ser443Pro, were discovered. The substitution Ala448Thr was found in terbinafine‐sensitive and terbinafine‐resistant isolates but was associated with increased MICs of itraconazole and voriconazole. Conclusions The high frequencies of terbinafine resistance in dermatophytes are worrisome and demand monitoring and further research. Squalene epoxidase substitutions between Leu393 and Ser443 could serve as markers of resistance in the future.

Indian Trichophyton mentagrophytes squalene epoxidase erg1 double mutants show high proportion of combined fluconazole and terbinafine resistance

“…6 So far, only few cases have been reported in Germany 7,8 but rising number can be expected prospectively. A proportion of Indian Trichophyton strains exhibit also resistance against itraconazole, voriconazole 3,5 or fluconazole. 3,4 The molecular mechanism of the azole resistance presently needs further investigation.…”

“…MLN allowed the characterisation of T mentagrophytes mutants, which all belong to ITS type VIII and differ in point mutation of Erg1. All strains were obtained from Delhi, North region from India,5 to get a homogenous fungal population.Erg1 point mutation at amino acid position Phe397Leu and Leu393Phe leads to high resistance against terbinafine and was found in nearly equal amounts in the Indian strain collection over a time span from 2015 to 2017. 3 In contrast, strains collected in the following years (2017-2019) and from all parts of India most frequently demonstrated Phe397Leu mutations (180 of 199 isolates, including double mutants) 5 and only few Phe393Leu mutants were identified (6 of 199 isolates).…”

Topical itraconazole formulations: Unscrupulous pharmaceutical companies and lax indian drug regulators endangering a precious drug

“…India has also witnessed the waning efficacy of terbinafine as an antifungal molecule over the past 5–7 years. Multiple studies from India and across the globe have documented high MIC values of terbinafine caused by squalene epoxidase mutations in this strain of T. mentagrophytes [ 17 18 19 20 21 22 ] [ Table 1 ]. Though studies regarding antifungal susceptibility patterns for itraconazole are few in comparison to terbinafine, several do point to itraconazole having an edge over other antifungals available in the Indian market.…”

“…Though studies regarding antifungal susceptibility patterns for itraconazole are few in comparison to terbinafine, several do point to itraconazole having an edge over other antifungals available in the Indian market. [ 17 18 ] With such a gloomy antifungal susceptibility pattern, to have multiple topical itraconazole formulations including one that also contains a superpotent corticosteroid and two antibacterial agents is a very dangerous development. [ 23 ] Itraconazole is deemed to be a highly effective antifungal drug for dermatologists in the systemic treatment of recalcitrant dermatophytosis and deep mycosis and for internists in managing various invasive/systemic fungal infections.…”

Belgian National Survey on Tinea Capitis: Epidemiological Considerations and Highlight of Terbinafine-Resistant T. mentagrophytes with a Mutation on SQLE Gene

“…This confirms the need to be careful regarding the emergence of dermatophytes resistant to terbinafine that occur not only in humans but also in animals, which can rapidly give rise to extended outbreaks. Squalene epoxidase substitutions between Leu393 and Ser443 could serve as markers of resistance in the future, as suggested by a recent paper from a multicenter study conducted in India [55]. In this recent paper, two novel substitutions in resistant Trichophyton strains, Ser395Pro and Ser443Pro, were discovered.…”