Reduced susceptibility mechanism to cefiderocol, a siderophore cephalosporin, among clinical isolates from a global surveillance programme (SIDERO-WT-2014)

Abstract

Objective: To investigate possible mechanistic factors to explain cefiderocol (CFDC) non-susceptibility, we characterized 38 clinical isolates with a CFDC minimum inhibitory concentration (MIC) of >4μg/mL from a multi-national surveillance study.

Methods: The MIC measurement in the presence of β-lactamase inhibitors and whole genome sequencing were performed.

Results: The MIC decrease of CFDC by β-lactamase inhibitors was observed against all of the test isolates. Among the 38 isolates, NDM and PER genes were observed in 5 and 25 isolates, respectively. No other β-lactamases responsible for high MIC were identified in the other eight isolates. The MIC of CDFC against Escherichia coli isogenic strains introduced with NDM and PER β-lactamase increased by ≥16-fold, suggesting the contribution of NDM and PER to the non-susceptibility to CFDC. Against NDM producers, a ≥8-fold MIC increase was observed only when both serine- and metallo-type β-lactamase inhibitors were added. In addition, many of the PER or NDM producers remained susceptible to CFDC. These results suggested that the presence of only NDM or PER would not lead to non-susceptibility to CFDC and that multiple factors would be related to CFDC resistance.

Conclusion: Multiple factors including NDM and PER could be related to reduced susceptibility to CFDC.

Keywords: Cefiderocol; Cefiderocol non-susceptible; Gram-negative bacilli; PER-type β-lactamase; Siderophore cephalosporin.