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

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 >4 mu g/mL from a multi-national surveillance study. Methods: The MIC measurement in the presence of beta-lactamase inhibitors and whole genome sequencing were performed. Results: The MIC decrease of CFDC by beta-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 beta-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 beta-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 beta-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. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.