Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials

Abstract

The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a ≥ 4-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the ≥4-fold MIC increase. Mutations in β-lactamases or penicillin-binding protein (PBP) were identified in 4/14 isolates: one Enterobacter cloacae (amino acid [AA] substitution [A313P] in ACT-17); two Acinetobacter baumannii (one PBP3 AA substitution [H370Y], one with OXA-23 substitutions [N85I and P225S]); and one Pseudomonas aeruginosa (PDC-30 [4AA deletion "TPMA" position 316-319]). Cloning experiments using isogenic Escherichia coli strains containing wild-type and those mutant cephalosporinase enzymes show that the mutant enzymes may contribute to decreased susceptibility to cefiderocol. Pharmacokinetic data were available for nine patients, for whom cefiderocol exposures exceeded 100% fT > 4 × MIC_. No clear pattern between mutations and development or extent of MIC increases was observed. No mutations were identified in genes related to iron transport, including fiu, cirA, piuA/C, and pirA, among recovered Gram-negative isolates. Clinicaltrials.gov: APEKS-NP: NCT03032380; CREDIBLE-CR: NCT02714595.

Keywords: MIC increase; cefiderocol; mutation; resistance; susceptibility; whole-genome sequencing.