Establishment of epidemiological cutoff values for Fonsecaea pedrosoi, the primary etiologic agent of chromoblastomycosis, and eight antifungal medications.

Abstract

Chromoblastomycosis, a fungal neglected tropical disease, is acquired through traumatic inoculation and is clinically characterized by a chronic granulomatous infection of the skin and subcutaneous tissue. Fonsecaea pedrosoi is the most commonly reported etiologic agent globally. Itraconazole is considered first-line therapy, but successful treatment with terbinafine, voriconazole, and posaconazole has been reported. F. pedrosoi minimum inhibitory concentration (MIC) data are limited, and epidemiological cutoffs (ECVs) are lacking; such data are important to help monitor antifungal resistance trends and guide initial antifungal selection. Thus, we performed antifungal susceptibility testing (AFST) on F. pedrosoi isolates and determined the MIC distributions and ECVs. AFST on Fonsecaea pedrosoi isolates was conducted at six laboratories from October 2023 to June 2024. Species identification was previously confirmed by DNA sequence analysis. AFST was performed by CLSI M38 standard broth microdilution method for itraconazole, voriconazole, posaconazole, isavuconazole, ketoconazole, terbinafine, flucytosine, and amphotericin B. The ECVs were established using the iterative statistical method with ECOFFinder (version 2.1) following CLSI M57 guidelines. We analyzed MIC results from 148 Fonsecaea pedrosoi isolates. The calculated ECVs were itraconazole, 0.5 µg/mL; voriconazole, 0.5 µg/mL; posaconazole, 0.5 µg/mL; isavuconazole, 1 µg/mL; ketoconazole, bimodal, no ECV determined; terbinafine, 0.25 µg/mL; flucytosine, rejected; and amphotericin, 8 µg/mL. These Fonsecaea pedrosoi ECVs, obtained through a multicenter international effort, provide a baseline to better understand the in vitro antifungal susceptibility profile of this species and monitor resistance. Clinicians and researchers can use these values to detect non-wild-type isolates with reduced susceptibility, reevaluate therapeutic options, and investigate potential clinical resistance if treatment failure occurs.IMPORTANCEChromoblastomycosis is a neglected tropical disease caused by an environmental, dematiaceous fungus. This fungal disease is acquired after a break in the skin that allows the fungus to enter, leading to a chronic infection in the skin and subcutaneous tissue. It is difficult to treat and often requires years of antifungal treatment. Fonsecaea pedrosoi is the most reported causative agent globally. Limited antifungal susceptibility data exist for F. pedrosoi making interpreting minimum inhibitory concentration (MIC) results difficult. We performed antifungal susceptibility testing on 148 F. pedrosoi isolates to establish MIC distributions and epidemiologic cutoff values (ECVs) for eight antifungals, including those commonly used to treat chromoblastomycosis. The calculated ECVs for the commonly used antifungals itraconazole and terbinafine were 0.5 and 0.25 µg/mL, respectively. ECVs can be helpful in choosing potential treatment options for F. pedrosoi and monitoring antifungal resistance epidemiology.