1266 - Characterization of Shifts in Minimum Inhibitory Concentrations During Treatment with Cefiderocol or Comparators in the Phase 3 CREDIBLE-CR and APEKS-NP Studies

Background: Cefiderocol (CFDC) is a novel siderophore cephalosporin developed to treat serious carbapenem-resistant (CR) Gram-negative (GN) infections.

Methods: In CREDIBLE-CR (NCT02714595), adults with serious infections caused by CR GN pathogens received CFDC 2 g, q8h, 3-h infusion, or best available therapy (BAT). In APEKS-NP (NCT03032380), adults with nosocomial pneumonia received CFDC or high-dose, extended-infusion meropenem (each 2 g, q8h, 3-h infusion). All treatments were given for 7‒14 days (extendable to 21 days). Biospecimens were collected before the first dose of study drug and at subsequent visits for assessments, and minimum inhibitory concentrations (MIC) to various antibiotics, including CFDC and carbapenems, were determined. Isolates with an increased MIC were evaluated by RT-PCR or whole genome sequencing (WGS) for CFDC resistance-related genes or mutations. Results for genetically related isolates with an elevated MIC during therapy are shown.

Results: On-therapy ≥4-fold CFDC MIC increase was found in 12 out of 106 (CREDIBLE-CR; Table 1) and 7 out of 159 (APEKS-NP; Table 2) isolates, respectively. For most isolates, CFDC MIC increased by 4–8-fold but remained ≤4 µg/mL. Specific mutations which could explain CFDC MIC increases were found in only 3 isolates. Mutations in iron-transport related genes were not identified. Mutation in CFDC target gene PBP-3 was identified in 1 A. baumannii isolate. Class-C enzyme mutation was observed in 2 isolates (CREDIBLE-CR: PDC-30 in P. aeruginosa; APEKS-NP: ACT-17 in E. cloacae), although the contribution to CFDC MIC increase has not been confirmed. In the BAT arm in CREDIBLE-CR, 6 out of 46 isolates had ≥4-fold MIC increase; all post-treatment isolates were resistant to BAT agents (Table 1), although WGS was not conducted for these isolates. In the meropenem arm in APEKS-NP, 5 out of 164 isolates had ≥4-fold MIC increase (Table 2).Table 1. MIC changes in CREDIBLE-CR
Table 2. MIC changes in APEKS-NP


Conclusion: Among isolates with ≥4-fold MIC increase during CFDC treatment, actual CFDC MIC values remained relatively low for most isolates. Frequency of MIC increase in BAT or meropenem arms was similar to that of CFDC, but the magnitude was greater. Acquisition of contributory mechanism has not been identified except for the mutation in PBP 3 and some β-lactamases.