Correlation ofIn VitroSusceptibility Based on MICs and Squalene Epoxidase Mutations with Clinical Response to Terbinafine in Patients with Tinea Corporis/Cruris

Abstract

Recalcitrant dermatophytoses are on the rise in India. High MICs of terbinafine (TRB) and squalene epoxidase (SQLE) gene mutations conferring resistance inTrichophytonspp. have been recently documented. However, studies correlating laboratory data with clinical response to TRB in tinea corporis/cruris are lacking. For this study, we investigated the clinicomycological profile of 85 tinea corporis/cruris patients and performed antifungal susceptibility testing by CLSI microbroth dilution and SQLE mutation analysis of the isolates obtained and correlated these with the responses to TRB. Patients confirmed by potassium hydroxide (KOH) mounting of skin scrapings were started on TRB at 250 mg once a day (OD). If >50% clinical clearance was achieved by 3 weeks, the same dose was continued (group 1). If response was <50%, the dose was increased to 250 mg twice a day (BD) (group 2). If the response still remained below 50% after 3 weeks of BD, the patients were treated with itraconazole (ITR; group 3). Overall, skin scrapings from 64 (75.3%) patients yielded growth on culture. Strikingly, all isolates were confirmed to beTrichophyton interdigitaleisolates by internal transcribed spacer (ITS) sequencing. Thirty-nine (61%) of the isolates had TRB MICs of ≥1 µg/ml. Complete follow-up data were available for 30 culture-positive patients. A highly significant difference in modal MICs to TRB among the three treatment response groups was noted (P = 0.009). Interestingly, 8 of the 9 patients in group 3 harbored isolates exhibiting elevated TRB MICs (8 to 32 µg/ml) and SQLE mutations. The odds of achieving cure with TRB MIC < 1 µg/ml strains were 2.5 times the odds of achieving cure with the strain exhibiting MIC ≥1 µg/ml.

<p>Emergence of Terbinafine Resistant <em>Trichophyton mentagrophytes</em> in Iran, Harboring Mutations in the Squalene Epoxidase (<em>SQLE</em>) Gene</p>

“…19 The TRB MIC values in resistant TMTISG isolates from Iran and other countries varied in the range ≥1-≥32 μg/mL. [12][13][14][16][17][18] In the current report, similar to some other studies, 5,15,17,19 all TRB resistant isolates belonged to T. mentagrophytes species and ITS type VIII (5/28; 18%). Despite this, careful analysis of the literature revealed resistant Type II strains (Table 3).…”

“…To the extent of our knowledge, TRB resistance in TMTISG isolates has already been reported from at least eight Asian and European countries, including India, 5,12,14,15 Switzerland, 11,16 Japan, 13 Finland, 17 Denmark, 18 Bahrain, 19 Russia, 32 and Germany. 19 The TRB MIC values in resistant TMTISG isolates from Iran and other countries varied in the range ≥1-≥32 μg/mL.…”

“…9,10 Nonetheless, recent reports from India and some other Asian and European countries indicate that clinical/microbial TRB resistance now involves T. interdigitale and T. mentagrophytes. 5,[11][12][13][14][15][16][17][18][19] Since these fungi are essentially conspecific, 20 they can be treated together as the T. mentagrophytes/T. interdigitale species group (TMTISG).…”

Major challenges and perspectives in the diagnostics and treatment of dermatophyte infections

“…Mutations in the gene encoding squalene epoxidase lead to structural changes in the enzyme and reduction of terbinafine protein binding without causing disturbances in ergosterol biosynthesis (Martinez-Rossi et al 2008). So far, many terbinafine-resistant T. rubrum, T. interdigitale and T. mentagrophytes clinical isolates have been described, and only several of them showed mutations associated with this gene (Martinez-Rossi et al 2008;Yamada et al 2017;Khurana et al 2018;Rudramurthy et al 2018). Interestingly, these isolates were resistant to all of the squalene epoxidase inhibitors tested, and molecular mutations were shown to occur in the same region in which they were identified in terbinafine-resistant S. cerevisiae strains (Martinez-Rossi et al 2008).…”

Multidrug therapy with terbinafine plus daily fluconazole is more effective than terbinafine alone or terbinafine plus weekly fluconazole in current epidemic of altered dermatophytosis in India: Results of a randomized pragmatic trial

“…6 Decreased effectiveness of terbinafine has been attributed to mutation in the squalene epoxidase gene. 7,8 Importance of finding effective methods of treating tinea cannot be overemphasized.…”