2113. Evaluation of Isavuconazole Activity against Aspergillus fumigatus Causing Invasive Infections Worldwide Using the New CLSI Clinical Breakpoints
Authors: Carvalhaes Cecilia G , Rhomberg Paul , Klauer Abby L , Hatch Beth , Castanheira Mariana 
Published: November 2023

Abstract

Background
Isavuconazole (ISC) was approved by the US FDA and is considered first-line therapy for the treatment of invasive aspergillosis (IA). Azole resistance in Aspergillus fumigatus (AFM) is a growing concern, mainly caused by mutations within CYP51 genes. The activity of ISC and other azoles against AFM causing IA worldwide was evaluated by applying the new CLSI ISC clinical breakpoints (BP).

Methods
A total of 846 AFM collected (1/patient) in 2017–2021 from 44 medical centers located in North America (NA; n=282; 18 centers), Europe (EU; n=449; 17 centers), Asia-Pacific (AP; n=102; 8 centers), and Latin America (LA, n=13; 1 center) were identified by MALDI-TOF MS and/or sequencing and tested by CLSI broth microdilution. CLSI BP and epidemiological cut-off values were applied where available. Isolates displaying a non-wildtype (NWT) phenotype to at least 1 azole were submitted to CYP51 analysis by whole genome sequencing.

Results
Overall, ISC (MIC50/90, 0.5/1 mg/L) showed similar activity to other azoles against AFM (Table), inhibiting 93.4% at ≤ 1 mg/L (CLSI-approved susceptible [S] BP). Voriconazole (VRC; MIC50/90, 0.5/0.5 mg/L), itraconazole (ITC; MIC50/90, 1/1 mg/L), and posaconazole (PSC; MIC50/90, 0.25/0.5 mg/L) inhibited 91.6%, 92.0%, and 97.2% at their respective S or wildtype criteria. The AZ-NWT phenotype was detected in 88 AFM (10.4%); NA showed the highest frequency of AZ-NWT isolates (31; 11.0%), followed by EU (48; 10.7%) and AP (9; 8.8%). No AZ-NWT AFM was noted in LA. Azole activity varied against AZ-NWT isolates with and without CYP51 alterations. Applying CLSI BPs, 43.9% of the AZ-NWT AFM without CYP51 alteration remained S to ISC and 73.2% were S to VRC. ISC and VRC inhibited 46.7% and 43.3%, respectively, of AZ-NWT AFM isolates displaying CYP51 alterations other than L98H/TR34 at the respective BP. AFM isolates carrying L98H/TR34 (17 occurrences) in the CYP51A sequence displayed elevated MIC ranges for all azoles: ISC, 2– &gt; 8 mg/L; VRC, 1– &gt; 8 mg/L; ITC, 2– &gt; 8 mg/L; and PSC, 0.5–4 mg/L.

Conclusion
ISC demonstrated potent in vitro activity against AFM regardless of the region and remained active against &gt; 40% of AZ-NWT AFM isolates displaying wildtype CYP51 sequences or carrying CYP51 alterations other than L98H/TR34.

Disclosures
Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), bioMerieux: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Abby L. Klauer, BS, Pfizer: Grant/Research Support Beth Hatch, BA MT(ASCP), Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support