Establishment of epidemiological cutoff values against Purpureocillium lilacinum

ABSTRACT Purpureocillium lilacinum , a common environmental fungus, can cause hyalohyphomycosis with varied clinical manifestations. Mortality rates can reach 20% with invasive disease. P. lilacinum is intrinsically resistant to amphotericin B, leaving few treatment options. In the absence of clinical breakpoints, epidemiological cutoff values (ECVs) can aid clinicians in monitoring antifungal resistance trends and in guiding initial therapy. We performed antifungal susceptibility testing (AFST) on P. lilacinum isolates to establish minimum inhibitory concentration (MIC) and minimum effective concentration (MEC) distributions and ECVs. Data were collected from 13 laboratories located in seven countries. AFST was performed by broth microdilution (CLSI M38 standard) for itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine, flucytosine, amphotericin B, natamycin, and manogepix. ECVs were established using the iterative statistical method with ECOFFinder (v2.1) following CLSI M57 guidelines. Results from 479 P. lilacinum isolates were analyzed. ECVs were 1 μg/mL for voriconazole, 2 μg/mL for posaconazole, 4 μg/mL for isavuconazole, and 2 μg/mL for terbinafine. Itraconazole displayed a trimodal MIC distribution, although almost all MICs were ≥0.5 µg/mL (mode, 16 μg/mL). Amphotericin B, natamycin, and flucytosine MICs were truncated at the high end of the range and consistent with intrinsic resistance. The manogepix modal MEC was 0.008 μg/mL. These proposed P. lilacinum ECVs and MIC/MEC distributions provide baseline data to monitor resistance trends. Our results confirm that P. lilacinum is intrinsically resistant (IR) to amphotericin B and likely IR to natamycin and flucytosine. Caution is needed in interpreting itraconazole results due to high interlaboratory variability. IMPORTANCE Purpureocillium lilacinum is a hyaline mold commonly found in the environment and used as an agricultural biopesticide. Infections caused by P. lilacinum can range from fungal eye infections to life-threatening pulmonary and disseminated disease, and mortality rates can be high (up to 20%). Single-center studies examining antifungal susceptibility testing (AFST) data found reduced susceptibility to certain antifungals, but more robust global AFST studies are needed to help interpret MICs and MECs. We performed AFST according to the Clinical Laboratory and Standards Institute reference method in thirteen independent laboratories on 479 P. lilacinum isolates to establish MIC/MEC distributions and epidemiological cutoff values (ECVs) for nine antifungals, including those recommended by global treatment guidelines. The calculated ECVs were 1 μg/mL for voriconazole, 2 μg/mL for posaconazole, 4 μg/mL for isavuconazole, and 2 μg/mL for terbinafine. Our results also confirm that P. lilacinum is intrinsically resistant to amphotericin B and likely intrinsically resistant to natamycin and flucytosine. Caution is needed in interpreting itraconazole AFST results due to high interlaboratory variability. These antifungal in vitro susceptibility data suggest limited options to treat P. lilacinum infections.