Untitled Synopsis: 1. A review of two cases of recalcitrant dermatophytosis which highlight a growing community health concern of antifungal- resistant Trichophyton species. 2. Highlight important clinical and diagnostic findings to consider when treating antifungal resistant dermatophytosis. 3. Utilization of fungal culture and antifungal susceptibility testing is imperative to aggressively treat and halt the spread of multidrug resistant tinea, especially for those with recurrent disease.. Patient A 24-year-old male with a 5+ year history of persistent dermatophytosis. • Exam findings: erythematous scaly plaques with central areas of clearing and active borders on the buttocks, left elbow, right hand, face. (Figure 1.1) • Social history: lived part-time in India and extensive intercontinental travel history for work • Prior work-up: previous biopsies showed dermatophytosis. No fungal culture had been sent per medical record review. • Failed treatments: several courses of oral terbinafine prescribed over 5 years. • On initial exam, skin scraping with KOH was inconclusive. Fungal culture was sent and grew T. mentagrophytes type viii. • Speciation and susceptibility reported in Table 1 highlighting terbinafine resistance. • Patient was treated with fluconazole 200 mg daily, econazole 2% cream, & ciclopirox shampoo. Conclusion There is a growing concern regarding the increase in the incidence of resistance development of dermatophytes against terbinafine. The presented cases illustrate the growing epidemiological trend of antifungal- resistant dermatophytosis in the US. These cases illustrate the growing epidemiological trend of antifungal- resistant dermatophytosis. This warrants a change in dermatologists’ clinical practices to 1) consider drug resistance in recalcitrant cases of dermatophytosis 2) evaluate the utility of fungal culture and interpreting antifungal susceptibility testing to isolate resistant species 3) practice antifungal stewardship and treat aggressively. Patient B 46-year-old male with a 10+ year history of recalcitrant dermatophytosis. • Exam findings: erythematous scaly coalescing papules and plaques with active erythematous borders on the posterior thighs, abdomen, buttocks (Figure 2.1) • Prior failed treatments: terbinafine, itraconazole, fluconazole without improvement. • Fungal cultures grew T. rubrum, Figure 2.2 • Speciation and susceptibility: reported in Table 2 revealed terbinafine, itraconazole, and fluconazole resistance. Posaconazole and griseofulvin susceptible. • Additional failed treatment: griseofulvin 250 mg three times daily x 3 months • Secondary treatment: Posaconazole 300 mg daily x 6 weeks. Figure 1.1 Patient A: buttocks and left shoulder References Terbinafine-resistant dermatophytosis in Alabama: two cases of recalcitrant dermatophytosis and the dermatologist’s role in detection of drug resistance and antifungal stewardship Callie Hill MD1, Mahmoud Ghannoum PhD3 , Natalie Garcia MS 2, Boni Elewski MD1 University of Alabama at Birmingham Hospital, Department of Dermatology 1 University of Alabama at Birmingham, School of Medicine 2 University Hospitals Cleveland Medical Center3 Table 1. Susceptibility Report with Minimum Inhibitory Concentrations (MIC) (μg/mL) for Patient A highlighting T. mentagrophytes resistance to terbinfafine . Figure 2.1 Patient B: lower abdomen and posterior thighs Table 2. Susceptibility Report with Minimum Inhibitory Concentrations (MIC) (μg/mL) for Patient B highlighting T. rubrum resistance to terbinafine, itraconazole, and fluconazole (2019-936). . Introduction We define recalcitrant dermatophytosis as insufficient response to an adequate antifungal course in a patient with microscopy or culture proven tinea infection. • New species, including T. mentagrophytes type viii, are spreading worldwide, initially from India and now reported in Birmingham, AL.1 • Innate terbinafine resistance vs. the widespread use of corticosteroids and topical antifungals in India is theorized to have resulted in T. mentagrophytes • Single nucleotide polymorphisms (SNPs) in the squalene epoxide (SE) gene in Trichophyton species leads to terbinafine resistant isolates • Evolving drug resistant dermatophyte species and lack of new treatments pose an increasing public health burden.2 • The minimum inhibitory concentration (MIC) is defined as the lowest concentration of a drug which inhibits microorganism growth. • The Clinical and Laboratory Standards Institutes (CLSI) has not published standardized guidelines for antifungal resistance in dermatophytes. However, a MIC of >0.5 μg/mL for terbinafine is considered elevated.3 ○ The break points for itraconazole against Candida species are as followed: MIC of ≤0.125 μg/ml is considered susceptible, 0.25 to 0.5 is susceptible dose dependent and greater or equal to 1 is resistant. ○ The break points for fluconazole against Candida species are as followed: MIC of ≤8 μg/mL is susceptible, 16-32 μg/mL is susceptible dose dependent and greater or equal to 64 is resistant.4 Current Systemic Antifungal Treatment Options • Terbinafine 250 mg daily • Fluconazole 200 mg daily • Itraconazole 200 mg daily • Griseofulvin (ultramicronized) 300-375 mg/daily • Posaconazole (off-label) 300mg daily **Add topical antifungals from a different class. If oral azole- use topical allylamine (terbinafine) or ciclopirox. Figure 1.2: Fungal culture growing T. mentagrophytes type viii on potato agar Figure 2.2: Fungal culture growing T. rubrum on potato agar 1. Ebert A, Monod M, Salamin K, Burmester A, Uhrlaß S, Wiegand C, Hipler UC, Krüger C, Koch D, Wittig F, Verma SB, Single A, Gupta S, Vasani R, Saraswat A, Madhu R, Panda S, Das A, Kura MM, Kumar A, Poojary S, Schirm S, Gräser Y, Paasch U, Nenoff P. Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study. Mycoses. 2020 Jul;63(7):717-728. doi: 10.1111/myc.13091. Epub 2020 May 4. PMID: 32301159.Saunte, Ditte M. .., et al. “Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection.” Antimicrobial Agents and Chemotherapy, vol. 63, no. 10, American Society for Microbiology, 2019, https://doi.org/10.1128/AAC.01126-19. 2. Taghipour S, Shamsizadeh F, Pchelin IM, Rezaei-Matehhkolaei A, Zarei Mahmoudabadi A, Valadan R, Ansari S, Katiraee F, Pakshir K, Zomorodian K, Abastabar M. Emergence of Terbinafine Resistant Trichophyton mentagrophytes in Iran, Harboring Mutations in the Squalene Epoxidase (SQLE) Gene. Infect Drug Resist. 2020 Mar 13;13:845-850. doi: 10.2147/IDR.S246025. PMID: 32214830; PMCID: PMC7078656. 3. Barros, Maria Elisabete da Silva, et al. “Evaluation of Susceptibility of Trichophyton Mentagrophytes and Trichophyton Rubrum Clinical Isolates to Antifungal Drugs Using a Modified CLSI Microdilution Method (M38-A).” Journal of Medical Microbiology, vol. 56, no. 4, Soc General Microbiol, 2007, pp. 514–18, https://doi.org/10.1099/jmm.0.46542-0. 4. Clinical and Laboratory Standards Institute (2002). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi, approved standard M38-A. Wayne, PA: Clinical and Laboratory Standards Institute Table 2: MIC (μg/mL) and FICI Results of T. mentagrophytes against Itraconazole, Fluconazole and Combination of Itraconazole and Fluconazole. https://doi.org/10.1128/AAC.01126-19 https://doi.org/10.1099/jmm.0.46542-0