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Background Cefiderocol (CFDC) is a siderophore cephalosporin with broad coverage of aerobic Gram-negative (GN) bacteria. Provisional breakpoints (BP) were approved by CLSI in 2018, with FDA and EUCAST providing clinical BP in 2019 and 2020, respectively; however, BPs differ markedly between organizations, reflecting differences in labelling, PK/PD standards and availability of clinical study data during regulatory review. Here we compare susceptibility rates based on these different BPs. Methods Susceptibility rates for each bacterial species were determined using CFDC BP from each organization and the MICs of 28,629 GN clinical isolates from 3 consecutive years of SIDERO-WT surveillance studies (2014–17). The analysis used all isolates and sub-grouped isolates based on meropenem (MEM) susceptibility (CLSI BP) or carbapenemase production. Results Within the overall Enterobacterales group, ≥98.5% isolates were interpreted as susceptible to CFDC regardless of BP used. However, the proportion of susceptible differed significantly (82.5–98.6%) when applied to MEM-non-susceptible (NS) isolates. Similarly, against most carbapenemase producers, susceptibility ranged from 80 to 100%, however for NDM producers, only 51% of isolates were defined as susceptible by FDA or EUCAST BP vs 84% using the CLSI BP. Against Pseudomonas aeruginosa including MEM-NS isolates, susceptibility was ≥94% despite different BPs recommended by FDA (1 mg/L), EUCAST (2 mg/L) and CLSI (4 mg/L). This changed the proportion of IMP-producing isolates classified as susceptible from 100% (CLSI) and 81% (EUCAST) to only 19% (FDA). Against other non-fermenters, susceptibility was ≥91% irrespective of BP used. Table 1. Susceptibility rates against Enterobacterales based on breakpoints from each organization Table 2. Susceptibility rates against non-fermenters based on breakpoints from each organization Conclusion Differences in BPs between FDA, CLSI and EUCAST could impact on the reporting of susceptibility or resistance to CFDC, particularly for MEM-NS isolates. PK/PD model simulations support 100% fT &amp;gt;MIC up to an MIC of 4 mg/L, and in Phase 3 trials the mean trough concentration of unbound cefiderocol was &amp;gt;4 mg/L. The potential impact of these differences on clinical decision making are important as the greatest clinical utility for CDFC is expected to be in patients with carbapenem-resistant GN infections due to limited treatment options. Disclosures Yoshinori Yamano, PhD, Shionogi &amp; Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi &amp; Co., Ltd. (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

1269. Differences in Interpretative Breakpoints Between CLSI, FDA and EUCAST Impact Reporting of Susceptibility and Resistance to Cefiderocol