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

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 >MIC up to an MIC of 4 mg/L, and in Phase 3 trials the mean trough concentration of unbound cefiderocol was >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.