| Summary: | Isavuconazole is the only US FDA-approved antifungal for treating invasive mucormycosis. We evaluated isavuconazole activity against a global collection of Mucorales isolates. Fifty-two isolates were collected during 2017–2020 from hospitals located in the USA, Europe, and the Asia-Pacific. Isolates were identified by MALDI-TOF MS and/or DNA sequencing and susceptibility tested by the broth microdilution method following CLSI guidelines. Isavuconazole (MIC<sub>50/90</sub>, 2/>8 mg/L) inhibited 59.6% and 71.2% of all Mucorales isolates at ≤2 mg/L and ≤4 mg/L, respectively. Among comparators, amphotericin B (MIC<sub>50/90</sub>, 0.5/1 mg/L) displayed the highest activity, followed by posaconazole (MIC<sub>50/90</sub>, 0.5/8 mg/L). Voriconazole (MIC<sub>50/90</sub>, >8/>8 mg/L) and the echinocandins (MIC<sub>50/90</sub>, >4/>4 mg/L) had limited activity against Mucorales isolates. Isavuconazole activity varied by species and this agent inhibited at ≤4 mg/L 85.2%, 72.7%, and 25% of <i>Rhizopus</i> spp. (<i>n</i> = 27; MIC<sub>50/90</sub>, 1/>8 mg/L), <i>Lichtheimia</i> spp. (<i>n</i> = 11; MIC<sub>50/90</sub>, 4/8 mg/L), and <i>Mucor</i> spp. (<i>n</i> = 8; MIC<sub>50</sub>, >8 mg/L) isolates, respectively. Posaconazole MIC<sub>50/90</sub> values against <i>Rhizopus</i>, <i>Lichtheimia</i>, and <i>Mucor</i> species were 0.5/8 mg/L, 0.5/1 mg/L, and 2/- mg/L, respectively; amphotericin B MIC<sub>50/90</sub> values were 1/1 mg/L, 0.5/1 mg/L, and 0.5/- mg/L, respectively. As susceptibility profiles varied among Mucorales genera, species identification and antifungal susceptibility testing are advised whenever possible to manage and monitor mucormycosis.
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