Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 66, Issue 2, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.02011-21
Keywords
Enterobacter cloacae; Enterobacterales; antibiotic resistance; carbapenem resistance; cefiderocol; cefiderocol resistance; drug resistance mechanisms; New Delhi metallo-beta-lactamase
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Funding
- Department of Infectious Diseases, Heidelberg University Hospital
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This study found that the emergence of resistance to Cefiderocol in metallo-beta-lactamase-producing bacteria is facilitated by mutations in the CirA siderophore receptor, which are induced by the New Delhi metallo-beta-lactamase. However, inhibiting the metallo-beta-lactamase activity using dipicolinic acid can successfully prevent the development of Cefiderocol-resistant mutants. Therefore, caution should be taken when using Cefiderocol to treat infections caused by metallo-beta-lactamase-producing bacteria.
Cefiderocol is a promising novel siderophore cephalosporin for the treatment of multidrug-resistant Gram-negative bacilli and with stability against degradation by metallo-p-lactamases. Nonetheless, the emergence of cefiderocol in metallo-beta-lactamase-producing Enterobacterales during therapy has been reported on more than one occasion. To understand the underlying mechanisms and factors facilitating the resistance development, we conducted an in vitro evolution experiment using clinical E. cloacae isolates via serial passaging under cefiderocol pressure. In this study, we showed that the presence of the New Delhi metallo-beta-lactamase (NDM) facilitates the emergence of resistance via nonsynonymous mutations of the CirA catecholate siderophore receptor. Inhibition of metallo-beta-lactamase activity using dipicolinic acid prevented the emergence of cefiderocol-resistant mutants successfully. This finding implies that caution should be taken when using cefiderocol for the treatment of infections caused by metallo-beta-lactamase-producing bacteria.
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