New Delhi Metallo-Beta-Lactamase Facilitates the Emergence of Cefiderocol Resistance in Enterobacter cloacae

Abstract

Cefiderocol is a promising novel siderophore cephalosporin for the treatment of multi-drug resistant Gram-negative bacilli and with stability against degradation by metallo-β-lactamases. Nonetheless, the emergence of cefiderocol in metallo-β-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 show that the presence of the New-Delhi metallo-β-lactamase (NDM) facilitates the emergence of resistance via non-synonymous mutations of the CirA catecholate siderophore receptor. Inhibition of metallo-β-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-β-lactamase- producing bacteria.

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance

“…The study flow chart is depicted in Figure 1 . A total of n = 52 relevant studies were reviewed [ 12 , 14 , 15 , 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. All studies were published after 2018; n = 17 (33%) in 2022, n = 18 (35%) in 2021, n = 12 (23%) in 2020, n = 1 (2%) in 2019, and n = 4 (8%) in 2018.…”

“…All studies were published after 2018; n = 17 (33%) in 2022, n = 18 (35%) in 2021, n = 12 (23%) in 2020, n = 1 (2%) in 2019, and n = 4 (8%) in 2018. Evaluation of mechanisms of resistance was based on: n = 13 group 1 studies [ 14 , 17 , 27 , 29 , 30 , 37 , 45 , 52 , 53 , 54 , 61 , 63 , 64 ], n = 4 group 2 studies [ 12 , 15 , 19 , 62 ], n = 11 group 3 studies [ 14 , 16 , 21 , 24 , 25 , 32 , 42 , 43 , 44 , 55 , 59 ], n = 7 group 4 studies [ 28 , 31 , 40 , 46 , 57 , 58 , 60 ], and n = 13 group 5 studies [ 29 , 31 , 41 , 47 , 48 , 49 , 50 , 51 , 54 , 55 , 56 , 57 , 64 ] (see Section 4.2 for grouping of studies). Data about the prevalence of heteroresistance were available in only two studies […”

Emergence of High-Level Cefiderocol Resistance in Carbapenem-Resistant Klebsiella pneumoniae from Bloodstream Infections in Patients with Hematologic Malignancies in China

“…Our results support previous findings that NDM confers greater MIC 50 values (2 μg/mL) than KPC, GES, IMP, VIM and OXA (0.12 - 1 μg/mL) ( 8 ) and NDM-producers showed an MIC distribution of cefiderocol with a higher concentration range compared with other carbapenemase producers ( 19 ). Interestingly, a recent study demonstrated that NDM but not KPC-2 and OXA-48 facilitate the acquisition of CirA mutation ( 20 ). Further kinetic parameters are required to explain the superiority of NDM.…”

“…Coincidentally, the E. cloacae strain was also NDM-5 positive. Further in vitro evolution experiments revealed that NDM-5 facilitates the emergence of CirA mutation, resulting in cefiderocol resistance in Enterobacter cloacae ( 20 ). The similar findings were also reported in K. pneumoniae recently ( 23 ).…”

Treatment of Severe Infections Due to Metallo-Betalactamases Enterobacterales in Critically Ill Patients

“…In an in vitro evolution experiment using clinical NDM- Enterobacter cloacae isolates via serial passaging, cefiderocol pressure leads to resistance acquisition. It was suggested that the presence of NDM facilitates the emergence of resistance via non-synonymous mutations of the CirA catecholate siderophore receptor [ 35 ].…”