Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae

Abstract

Importance: Trichophyton indotineae is an emerging dermatophyte causing outbreaks of extensive tinea infections often unresponsive to terbinafine. This species has been detected worldwide and in multiple US states, yet detailed US data on infections with T indotineae are sparse and could improve treatment practices and medical understanding of transmission.

Objective: To correlate clinical features of T indotineae infections with in vitro antifungal susceptibility testing results, squalene epoxidase gene sequence variations, and isolate relatedness using whole-genome sequencing.

Design, setting, and participants: This retrospective cohort study of patients with T indotineae infections in New York City spanned May 2022 to May 2023. Patients with confirmed T indotineae infections were recruited from 6 New York City medical centers.

Main outcome and measure: Improvement or resolution at the last follow-up assessment.

Results: Among 11 patients with T indotineae (6 male and 5 female patients; median [range] age, 39 [10-65] years), 2 were pregnant; 1 had lymphoma; and the remainder were immunocompetent. Nine patients reported previous travel to Bangladesh. All had widespread lesions with variable scale and inflammation, topical antifungal monotherapy failure, and diagnostic delays (range, 3-42 months). Terbinafine treatment failed in 7 patients at standard doses (250 mg daily) for prolonged duration; these patients also had isolates with amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase that correlated with elevated terbinafine minimum inhibitory concentrations of 0.5 μg/mL or higher. Patients who were treated with fluconazole and griseofulvin improved in 2 of 4 and 2 of 5 instances, respectively, without correlation between outcomes and antifungal minimum inhibitory concentrations. Furthermore, 5 of 7 patients treated with itraconazole cleared or had improvement at the last follow-up, and 2 of 7 were lost to follow-up or stopped treatment. Based on whole-genome sequencing analysis, US isolates formed a cluster distinct from Indian isolates.

Conclusion and relevance: The results of this case series suggest that disease severity, diagnostic delays, and lack of response to typically used doses and durations of antifungals for tinea were common in this primarily immunocompetent patient cohort with T indotineae, consistent with published data. Itraconazole was generally effective, and the acquisition of infection was likely in Bangladesh.

Figure 1.. Trichophyton indotineae Causing Tinea Corporis

The patient was treated with 6 weeks of itraconazole, 100 mg twice daily.

Figure 2.. Trichophyton indotineae Isolates from New York City (NYC)

A k-mer analysis was conducted in CLC Genomics Workbench using assembled genomes from 11 isolates recovered from patients in New York City, 8 publicly available Indian T indotineae genomes, and 1 publicly available T interdigitale genome from an isolate originating from Germany. K-mers with a prefix of ATGAC and a length of 16 on either strand were included in the analysis. The scale bar for branch length indicates the level of similarity in k-mer distribution among isolates. These isolates form a cluster distinct from T indotineae isolates from India.

Figure 3.. Relatedness Among New York City Trichophyton indotineae Isolates

A, New York City T indotineae isolate sequencing reads were mapped to the Indian T indotineae reference isolate TIMM20114, and a phylogenetic tree was generated using a maximum likelihood algorithm with a Juke-Cantor nucleotide substitution model and 1000 bootstrap replicates. Bootstrap values on branches indicate the percentage likelihood that a particular branching pattern is correct. The scale bar shows the number of substitutions/changes per nucleotide. Terbinafine minimum inhibitory concentration (MIC) values and squalene epoxidase (SQLE) variants for each isolate are indicated by the red and blue bars to the right of the phylogenetic tree, respectively. B, Pairwise single nucleotide variation matrix of New York City T indotineae isolates. Single nucleotide variation values are color-coded along a gradient from low (blue) to high (pink). The outbreak isolates are shown from patients A to K.