Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in blaNDM-5 Copy Number and Gene Expression.

BACKGROUND: As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. METHODS: We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient. RESULTS: In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 µg/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later. CONCLUSIONS: The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.