Emergence of high-level aztreonam–avibactam and cefiderocol resistance following treatment of an NDM-producing Escherichia coli bloodstream isolate exhibiting reduced susceptibility to both agents at baseline

Abstract Background Cefiderocol (FDC) or ceftazidime-avibactam with aztreonam (CZA-ATM) are frontline agents for New Delhi metallo-β-lactamase (NDM)-producing Enterobacterales; however, clinical data are scarce, and mechanisms of treatment-emergent resistance are ill-defined. Our objectives were to characterize serial isolates and stool microbiota from a liver transplant recipient with NDM-producing Escherichia coli bacteraemia. Methods Isolates collected pre- and post-CZA–ATM treatment underwent broth microdilution susceptibility testing and whole-genome sequencing. Longitudinal stool collected during CZA–ATM therapy underwent metagenomic sequencing (Nanopore MinION). Results The baseline isolate exhibited elevated MICs for ATM–AVI (16/4 µg/mL) and FDC (8 µg/mL). Posttreatment, a rectal surveillance isolate exhibited high-level resistance to ATM–AVI ( 128/4 µg/mL) and FDC (32 µg/mL). Both isolates belonged to ST361 and harboured WT blaNDM-5. The baseline isolate contained wild type (WT) blaCMY-145 and mutations in ftsI (which encodes PBP3), including a YRIN insertion at residue 338 and the non-synonymous substitutions Q227H, E353K and I536L. The posttreatment isolate harboured new mutations in ftsI (A417 V) and blaCMY-145 (L139R and N366Y). Analysis of four stool samples collected during CZA–ATM treatment revealed high E. coli abundance. E. coli relative abundance increased from 34.5% (first sample) to 61.9% (last sample). Conclusions Baseline mutations in ftsI were associated with reduced susceptibility to ATM–AVI and FDC in an ST361 NDM-5-producing E. coli bloodstream isolate. High-level resistance was selected after CZA–ATM treatment, resulting in new ftsl and blaCMY-145 mutations. These findings underscore the need for ATM–AVI susceptibility testing for NDM producers, and the potential for PBP3 mutations to confer cross-resistance to ATM–AVI and FDC, which can emerge after CZA–ATM treatment.