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Trichophyton indotineae has emerged as a novel dermatophyte species resulting in treatment recalcitrant skin infections. While the earliest reports came from India, T. indotineae has now spread to many parts of the world and is rapidly becoming a global health concern. Accurate identification of T. indotineae requires elaborate mycological investigations which is beyond the domain of routine microbiology testing. Extensive, non-inflammatory and atypical presentations are commonly seen with this novel species. T. indotineae shows an alarmingly high rate of mutations in the squalene epoxidase gene leading to lowered in vitro susceptibility to terbinafine. This has also translated into a lowered clinical response and requirement of a higher dose and much longer durations of treatment with the drug. Although the species remains largely susceptible to itraconazole, prolonged treatment durations are required to achieve cure with itraconazole. Fluconazole and griseofulvin do not have satisfactory in vitro or clinical activity. Apart from requirement of prolonged treatment durations, relapse postsuccessful treatment is a distressing and yet unexplained consequence of this "species-shift." Use of third generation azoles and combinations of systemic antifungals is unwarranted as both have not demonstrated clear superiority over itraconazole given alone, and the former is an important class of drugs for invasive mycoses., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

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., (© 2023 the International Society of Dermatology.)

Background: With rising resistance to terbinafine, and consistently high MICs to fluconazole and griseofulvin, itraconazole is being increasingly used as a first line drug for tinea corporis/cruris. However, inadequate clinical responses are often seen with it in spite of in vitro susceptibility. This is possibly related to a variable pharmacokinetic profile of itraconazole. The drug serum levels associated with the therapeutic outcome have not been defined in dermatophytic infections., Methods: Forty treatment naïve patients with tinea corporis/cruris were randomised to one of the three dose groups (100, 200 and 400 mg/day) of itraconazole. The drug serum levels of 21 of these patients were obtained after 2 weeks of treatment and correlated with the final clinical outcome and in vitro antifungal susceptibility data., Results: Trichophyton indotineae was identified by sequencing of ITS region of rDNA and TEF1α. All isolates were sensitive to itraconazole (Minimum Inhibitory Concentration (MICs) range: 0.06-0.5 µg/ml), while MICs to terbinafine were uniformly high (range 8-32 µg/ml). Thirty-seven patients (92.5%) achieved complete cure, while three failed treatment. Serum levels achieved with 400 mg/day were significantly higher than levels with 100 or 200 mg dose. All patients with itraconazole serum levels of >0.2 µg/ml were cured, while two out of the 10 patients with serum levels <0.2 µg/ml failed treatment., Conclusions: Therapeutic failures are uncommon with itraconazole, and the prevalent strain in India has low itraconazole MICs. Treatment failure is likely with itraconazole serum levels of <0.2 µg/ml, while levels >0.2 µg/ml are consistently associated with a positive therapeutic outcome., (© 2021 Wiley-VCH GmbH.)

Recalcitrant dermatophytosis has had an alarming rise in India with concomitant decreased effectiveness of conventional antifungal agents. This has prompted the use of second-line agents for treatment. In this retrospective study, we aimed to analyze the response rate, efficacy, relapse rate, and side effects of oral ketoconazole (KZ) in the treatment of recalcitrant tinea corporis and cruris. Institutional records were reviewed for patients presenting with tinea cruris or corporis who had failed treatment with conventional antifungal drugs and treated with oral KZ. Potassium hydroxide (KOH) findings, culture reports, and response to treatment was noted based on the percentage improvement in lesions and reduction in itching compared with baseline. Fourty-three patients (mean age 31.3 years) with tinea corporis/cruris who had taken prior treatment with antifungals were recruited in the study. KOH mount and culture were positive in 76.7% patients. Trichophyton mentagrophytes was the commonest species, isolated in 62.8% of patients. Ketoconazole showed the lowest minimum inhibitory concentration on antifungal susceptibility tests with various antifungals. With a dose of 400 mg daily, 67.4% of patients were cured of disease with mean duration of 9.4 weeks. Patients having less than 40% clearance at 2 weeks had a 68.9% less probability of getting cured of disease. Of the 29 patients cured, 37.9% relapsed because of various predisposing factors. Two patients developed increase in liver enzymes on treatment. Our analysis suggests that KZ can be used as alternative drug in cases with failure to conventional antifungal drugs. Though there are relapses, these can be partially explained by various predisposing factors that support fungal survival and transmission.

Recalcitrant dermatophytic infections of the glabrous skin (tinea corporis/cruris/faciei) pose a huge challenge to health care systems. Combinations of oral and topical drugs may potentially improve cure rates, but the same has never been objectively assessed for this condition in laboratory or clinical studies. The present study was undertaken with the aim of identifying synergistic combinations of oral and topical antifungals by testing clinical isolates obtained from patients with recalcitrant tinea corporis/cruris. Forty-two patients with tinea corporis/cruris who had failed oral antifungals or had relapsed within 4 weeks of apparent clinical cure were recruited. Twenty-one isolates were identified by sequencing (all belonging to the Trichophyton mentagrophytes/T. interdigitale species complex) and subjected to antifungal susceptibility testing (AFST) and squalene epoxidase (SQLE) gene mutation analysis. Finally, five isolates, four with underlying SQLE gene mutations and one wild-type strain, were chosen for checkerboard studies using various combinations of antifungal agents. Most isolates ( n  = 16) showed high MICs of terbinafine (TRB) (0.5 to >16 μg/ml), with SQLE gene mutations being present in all isolates with MICs of ≥0.5 μg/ml. Synergistic interactions were noted with combinations of itraconazole with luliconazole, TRB, and ketoconazole and propylene glycol monocaprylate (PGMC) with luliconazole and with the triple combination of PGMC with luliconazole and ketoconazole. In vitro synergistic interactions provide a sound scientific basis for the possible clinical use of antifungal combinations. Hence, these synergistic combinations may be tested for clinical utility in the wake of rising resistance among dermatophytic infections of the glabrous skin.

Nonprescription use of topical corticosteroids (TCS) is a significant concern. This can lead to cutaneous adverse effects, altered morphology of skin disorders and chronicity of cutaneous infections. To record and analyze the patterns of TCS use in patients with tinea corporis/cruris and analyze factors determining the development of cutaneous side effects. Hundred patients with a clinical diagnosis of tinea corporis/cruris who could recall the TCS preparation/s used were included. The TCS usage patterns were recorded and analyzed. Most patients had used very potent TCS (n = 66). Most reported using TCS intermittently for duration ranging from 1 to 4 weeks (n = 78). Relapse of symptoms occurred within 1 to 2 weeks of stopping TCS, triggering reuse. Cutaneous adverse effects were present in 44 patients (striae [n = 29], hypo/depigmentation [n = 11], skin thinning [n = 8], hypertrichosis [n = 1], tinea pseudoimbricata [n = 1]). There was a significant correlation between presence of cutaneous adverse effects and the total duration of TCS use (P = .0016), duration of disease (P = .016), and total amount of TCS used (P = .012). Use for >60 days and of >32 g were associated with 89% and 96.3% (respectively) probability of developing cutaneous adverse effects. Self-use of TCS is a worrisome trend. Intermittent use is a plausible reason for development of cutaneous side effects in only 44% patients., (© 2020 Wiley Periodicals LLC.)

Dermatophytoses or tinea refers to superficial fungal infection of keratinized tissues. Although generally considered easy to treat, recalcitrant infections, presenting as extensive and difficult to treat tinea corporis and cruris, are on the rise in some parts of the world. The situation demands an understanding of the pharmacokinetic and pharmacodynamic properties of the available antifungals against dermatophytes and the possible contribution of drug resistance and other factors to the present scenario. In this review, we provide the readers a comprehensive account of the available literature on in-vitro and in-vivo resistance to clinically used antifungals among dermatophytes. We have also added, in brief, the relevant skin pharmacokinetics of important systemic drugs. The established and postulated mechanisms of drug resistance are discussed and aspects on lack of in vivo correlation of in vitro resistance are presented. Finally, the lacunae in our existing knowledge on the topic and the arenas for future research are highlighted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Recalcitrant dermatophytoses is on the rise. Though myriad factors contribute to recalcitrance including terbinafine resistance, itraconazole largely remains sensitive. However, there are increasing instances of patients not responding adequately to itraconazole despite low MICs, probably due to issues plaguing the pelletization process, resulting in suboptimal quality. Data on this topic was searched on pubmed using the search items: itraconazole, MIC, MFC, quality, assay, pharmacokinetics, pharmacodynamics, dermatophytoses, and recalcitrance. Areas covered: A detailed analysis of the manufacturing process of itraconazole with emphasis on pelletization and parameters affecting the dissolution and bioavailability is presented. Important formulation factors including drug-polymer ratio, polymer type, coating thickness, bead size, and number are discussed. Also covered is the rationale of dosimetry of itraconazole in dermatophytoses based on the skin pharmacokinetics and MIC of the organism. Expert opinion: The process of pelletization has multiple components aiming to achieve maximum dissolution of the drug. Variations in the process, pellet quality, number, and polymer determine absorption. Morphometric analysis of pellets is a simple method to quantify quality of the drug. Once the process has been standardized, dosimetry depends on the route of secretion and site of infection, accounting for the variation of doses from 100 mg to 400 mg/day.

Recalcitrant dermatophytoses are on the rise in India. High MICs of terbinafine (TRB) and squalene epoxidase ( SQLE ) gene mutations conferring resistance in Trichophyton spp. 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 be Trichophyton interdigitale isolates 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., (Copyright © 2018 American Society for Microbiology.)

Background: Dermatophytosis management has become an important public health issue, with a large void in research in the area of disease pathophysiology and management. Current treatment recommendations appear to lose their relevance in the current clinical scenario. The objective of the current consensus was to provide an experience-driven approach regarding the diagnosis and management of tinea corporis, cruris and pedis., Methods: Eleven experts in the field of clinical dermatology and mycology participated in the modified Delphi process consisting of two workshops and five rounds of questionnaires, elaborating definitions, diagnosis and management. Panel members were asked to mark "agree" or "disagree" beside each statement, and provide comments. More than 75% of concordance in response was set to reach the consensus., Result: KOH mount microscopy was recommended as a point of care testing. Fungal culture was recommended in chronic, recurrent, relapse, recalcitrant and multisite tinea cases. Topical monotherapy was recommended for naïve tinea cruris and corporis (localised) cases, while a combination of systemic and topical antifungals was recommended for naïve and recalcitrant tinea pedis, extensive lesions of corporis and recalcitrant cases of cruris and corporis. Because of the anti-inflammatory, antibacterial and broad spectrum activity, topical azoles should be preferred. Terbinafine and itraconazole should be the preferred systemic drugs. Minimum duration of treatment should be 2-4 weeks in naïve cases and > 4 weeks in recalcitrant cases. Topical corticosteroid use in the clinical practice of tinea management was strongly discouraged., Conclusion: This consensus guideline will help to standardise care, provide guidance on the management, and assist in clinical decision-making for healthcare professionals.