868. In Vitro Activity of Isavuconazole and Other Mould-Active Triazoles Against Aspergillus fumigatus With and Without cyp51 Alterations. (15th December 2022) - Pfaller, Michael A
Abstract: Background: Azole resistance in Aspergillus fumigatus (AFM) is mainly associated with mutations in cyp51A and its promoter region or its homologue cyp51B . We evaluated the in vitro activity of isavuconazole (ISC), itraconazole (ITC), posaconazole (PSC), and voriconazole (VRC) against 660 AFM collected during 2017–2020. Methods: Isolates from Europe (EU), North America (NA), Latin America (LA), and Asia-Pacific (APAC) were identified by MALDI-TOF and/or sequencing and tested by CLSI broth microdilution. CLSI epidemiological cut-off values (ECV) were applied. A PSC ECV of 0.5 mg/L was used. Non-wildtype (NWT) isolates to azoles were screened for alterations in the cyp51 genes using whole genome sequencing. Results: Azoles had similar activities against 660 AFM isolates. Overall, AFM displayed WT MIC values to ISC (92.7%), ITC (92.9%), PSC (97.3%), and VRC (96.7%). Only 66 isolates (10.0%) were NWT to 1 or more of the azoles, and 32 harbored one or more alterations in the cyp51 genes. Of these AFM, 29/32 (90.1%) were NWT to ITC, 25/32 (78.1%) NWT to ISC, 17/32 (53.1%) NWT to VRC, and 11/32 (34.4%) NWT to PSC. The most frequent alteration was CYP51A TR34/L98H, carried by 14 EU isolates, all NWT to ISC and ITC. Four isolates from NA carried the alteration I242V in CYP51A (all NWT to ITC; all WT to ISC). One NA isolate carried the CYP51A alteration G448S (NWT to ISC, VRC, and ITC) and one carried A9T (NWT to ISC). A single isolate from APAC carried a CYP51A G138C alteration and was NWT to all 4 triazoles. Multiple alterations in CYP51A were detected in 5 isolates: 4/5 NWT to ISC or ITC, 1/5 NWT to VRC, all WT to PSC. Alterations in CYP51B were noted in 7 isolates; 6/7 carried Q42L, 3 from NA (all NWT to ITC and 2 NWT to ISC), 2 from APAC (all NWT to VRC or ISC), and 1 from EU (NWT to ISC, ITC, and PSC). Among 34 NWT isolates without cyp51 alterations, 32.4% were WT to ISC, 47.1% WT to ITC, 85.3% WT to VRC, and 82.4% WT to PSC. Conclusion: The majority of AFM were WT to azoles. Ten different cyp51 alterations were detected in 32/66 NWT isolates. Only EU isolates harboured the environmental alteration TR34/L98H that was associated with a NWT phenotype to ISC and ITC. Alterations in AFM cyp51 can have variable effects on the in vitro activity of the azoles that are best delineated by testing all triazoles. Disclosures: Michael A. Pfaller, MD, Pfizer: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), Cidara: Grant/Research Support|Pfizer: Grant/Research Support.