Defining Baseline Mechanisms of Cefiderocol Resistance in the Enterobacterales

Simner, Patricia J.; Beisken, Stephan; Bergman, Yehudit; Ante, Michael; Posch, Andreas E.

doi:10.1089/mdr.2021.0095

Cited by 39 publications

(50 citation statements)

References 40 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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 […”

Section: Resultsmentioning

confidence: 99%

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

2022

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Cefiderocol appears promising, as it can overcome most β-lactam resistance mechanisms (including β-lactamases, porin mutations, and efflux pumps). Resistance is uncommon according to large multinational cohorts, including against isolates resistant to carbapenems, ceftazidime/avibactam, ceftolozane/tazobactam, and colistin. However, alarming proportions of resistance have been reported in some recent cohorts (up to 50%). A systematic review was conducted in PubMed and Scopus from inception to May 2022 to review mechanisms of resistance, prevalence of heteroresistance, and in vivo emergence of resistance to cefiderocol during treatment. A variety of mechanisms, typically acting in concert, have been reported to confer resistance to cefiderocol: β-lactamases (especially NDM, KPC and AmpC variants conferring resistance to ceftazidime/avibactam, OXA-427, and PER- and SHV-type ESBLs), porin mutations, and mutations affecting siderophore receptors, efflux pumps, and target (PBP-3) modifications. Coexpression of multiple β-lactamases, often in combination with permeability defects, appears to be the main mechanism of resistance. Heteroresistance is highly prevalent (especially in A. baumannii), but its clinical impact is unclear, considering that in vivo emergence of resistance appears to be low in clinical studies. Nevertheless, cases of in vivo emerging cefiderocol resistance are increasingly being reported. Continued surveillance of cefiderocol’s activity is important as this agent is introduced in clinical practice.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

2022

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“…From the clinical point of view, cefiderocol is an important and promising drug due to its stability against metallo-β-lactamase-producing bacteria ( 9 ). To date, this antibiotic substance is not yet widely in clinical use, so that knowledge on the resistance mechanisms and the circumstances under which resistances can emerge is still limited ( 10 ). In a previous clinical case on in vivo emergence of cefiderocol resistance in Enterobacter cloacae during therapy, we demonstrated that, despite heterogeneity (deletion, insertion, and transposon insertion), the frameshift mutations in the cefiderocol-resistant E. cloacae isolates always targeted the cirA gene ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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

Nurjadi

Kocer

Chanthalangsy

et al. 2022

Antimicrob Agents Chemother

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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.

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“…Previous reports support a link between mutations in iron transporters and a decrease in susceptibility to CFDC [33,42,44]. In particular, PirA and PiuA have been linked with CFDC entry and CFDC resistance when mutations in these genes have been reported [33,34].…”

Section: Discussionmentioning

confidence: 84%

“…Simner et al explored possible resistance mechanisms to CFDC in 14 isolates of carbapenem-resistant Enterobacterales that exhibited baseline CFDC resistance (minimum inhibitory concentration (MICs) >/= 4 mg/L) [42]. They identified heterogeneous mechanisms that include the combination of β-lactamase production and permeability defects contributing to elevated CFDC MIC.…”

Section: Introductionmentioning

confidence: 99%

Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: Role of Iron Transport

Pimentel

Pasterán

et al. 2022

Biomedicines

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Cefiderocol, a recently introduced antibiotic, has a chemical structure that includes a cephalosporin that targets cell wall synthesis and a chlorocatechol siderophore moiety that facilitates cell penetration by active iron transporters. Analysis of the effect that human serum, human serum albumin, and human pleural fluid had on growing Acinetobacter baumannii showed that genes related to iron uptake were down-regulated. At the same time, β-lactamase genes were expressed at higher levels. The minimum inhibitory concentrations of this antimicrobial in A. baumannii cells growing in the presence of human serum, human serum albumin, or human pleural fluid were higher than those measured when these fluids were absent from the culture medium. These results correlate with increased expression levels of β-lactamase genes and the down-regulation of iron uptake-related genes in cultures containing human serum, human serum albumin, or human pleural fluid. These modifications in gene expression could explain the less-than-ideal clinical response observed in patients with pulmonary or bloodstream A. baumannii infections. The exposure of the infecting cells to the host’s fluids could cause reduced cefiderocol transport capabilities and increased resistance to β-lactams. The regulation of genes that could impact the A. baumannii susceptibility to cefiderocol, or other antibacterials, is an understudied phenomenon that merits further investigation.

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Defining Baseline Mechanisms of Cefiderocol Resistance in the Enterobacterales

Cited by 39 publications

References 40 publications

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

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

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

Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: Role of Iron Transport

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