Clinical Evolution of AmpC-Mediated Ceftazidime-Avibactam and Cefiderocol Resistance in <i>Enterobacter cloacae</i> Complex Following Exposure to Cefepime

Shields, Ryan K.; Iovleva, Alina; Kline, Ellen G; Kawai, Akito; McElheny, Christi L.; Doi, Yohei

doi:10.1093/cid/ciaa355

Cited by 63 publications

(49 citation statements)

References 15 publications

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“…Shields and colleagues demonstrated a 2–amino acid deletion in the R2 loop of the AmpC β-lactamase (ie, alanine and leucine at positions 292 and 293) in 2 Enterobacter hormaechei isolates from distinct patients after exposure to cefepime [ 9 ]. These deletions appear to broadly impact cephalosporin antibiotics in that they confer resistance to cefepime, CAZ-AVI, and cefiderocol—in the absence of preceding exposure to CAZ-AVI or cefiderocol.…”

Section: Discussionmentioning

confidence: 99%

“…Proteins associated with increased permeability were also assessed (OprD, mex-operon encoded proteins). Furthermore, based on reports of deletions, insertions, and amino acid substitutions in or proximal to the omega loop of AmpC contributing to cefiderocol resistance [ 9–11 ], this region was carefully examined. Bioinformatics analyses were conducted by Ares Genetics.…”

Section: Methodsmentioning

confidence: 99%

“…Before the clinical use of cefiderocol, there was widespread belief that resistance would primarily result from mutations in TonB-dependent receptors (TBDRs), a series of bacterial outer membrane proteins that mediate siderophore–iron complex transport [ 4-6 ]. While such mutations have been identified [ 7 , 8 ], there have also been isolated reports of changes in the ampC region contributing to cefiderocol resistance among the Enterobacterales [ 9 , 10 ]. This may occur after exposure to oxyminocephalosporins, such as CAZ-AVI or cefepime, in the absence of exposure to cefiderocol.…”

mentioning

confidence: 99%

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Cefiderocol Activity Against ClinicalPseudomonas aeruginosaIsolates Exhibiting Ceftolozane-Tazobactam Resistance

Simner

Beisken

Bergman

et al. 2021

Open Forum Infectious Diseases

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Objective Mutations in the AmpC-AmpR region are associated with treatment-emergent ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-avibactam (CAZ-AVI) resistance. We sought to determine if these mutations impact susceptibility to the novel cephalosporin-siderophore compound cefiderocol. Methods Thirty-two paired isolates from 16 patients with index P. aeruginosa isolates susceptible to TOL-TAZ and subsequent P. aeruginosa isolates available after TOL-TAZ exposure from January 2019 to December 2020 were included. TOL-TAZ, CAZ-AVI, imipenem-relebactam (IMI-REL), and cefiderocol minimum inhibitory concentrations (MICs) were determined using broth microdilution. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance to cefiderocol that emerged, focusing on putative mechanisms of resistance to cefiderocol or earlier siderophore-antibiotic conjugates based on the previously published literature. Results Analyzing the 16 pairs of P. aeruginosa isolates, ≥4-fold increases in cefiderocol MICs occurred in 4 of 16 isolates. Cefiderocol non-susceptibility criteria was met for only 1 of the 4 isolates, using Clinical and Laboratory Standards Institute criteria. Specific mechanisms identified included the following: AmpC E247K (2 isolates), MexR A66V and L57D (1 isolate each), and AmpD G116D (1 isolate) substitutions. For both isolates with AmpC E247K mutations, ≥4-fold MIC increases occurred for both TOL-TAZ and CAZ-AVI, while a ≥4-fold reduction in IMI-REL MICs was observed. Conclusions Our findings suggest that alterations in the target binding sites of P. aeruginosa derived AmpC β-lactamases have the potential to reduce the activity of three of four novel β-lactams (i.e., ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol) and potentially increase susceptibility to imipenem-relebactam. These findings are in need of validation in a larger cohort.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cefiderocol Activity Against ClinicalPseudomonas aeruginosaIsolates Exhibiting Ceftolozane-Tazobactam Resistance

Simner

Beisken

Bergman

et al. 2021

Open Forum Infectious Diseases

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“…A 4- to 32-fold increase of an MIC90 was observed in D179Y-H274Y mutations of KPC-31 compared to the wild-type alleles reported by Hobson et al in 2021 ( 35 ). Shields et al have reported that the deletion of positions 292 and 293, which are located in the R2 loop of AmpC, causes the decreased susceptibility of Enterobacterales ( 38 ). The mutations lead to the disappearance of the H10 helix in the R2 loop and the expansion of the substrate-binding site, resulting in a more stable binding to the bulkier side chain possessed by CFDC ( 38 ).…”

Section: Resistance Mechanismsmentioning

confidence: 99%

“…Shields et al have reported that the deletion of positions 292 and 293, which are located in the R2 loop of AmpC, causes the decreased susceptibility of Enterobacterales ( 38 ). The mutations lead to the disappearance of the H10 helix in the R2 loop and the expansion of the substrate-binding site, resulting in a more stable binding to the bulkier side chain possessed by CFDC ( 38 ). Akito et al have demonstrated the alanine-proline deletion at positions 294 and 295 located in the R2 loop, which is also associated with the reduced susceptibility to CFDC in E. coli and E. cloacae ( 39 ).…”

Section: Resistance Mechanismsmentioning

confidence: 99%

Cefiderocol: An Overview of Its in-vitro and in-vivo Activity and Underlying Resistant Mechanisms

Yao¹,

Wang²,

Chen³

et al. 2021

Front. Med.

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Treatment of multidrug-resistant (MDR) Gram-negative bacteria (GNB) infections has led to a global public health challenging due to the bacterial resistance and limited choices of antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin possessed unique drug delivery systems and stability to β-lactamases, has the potential to become first-line therapy for most aggressive MDR Gram-negative pathogens infection. However, there have been reports of drug resistance in the course of using CFDC. This study provides an overview of the in-vitro and in-vivo activity of CFDC and potential resistance mechanism was also summarized. In general, CFDC shows excellent activity against a broad range of MDR GNB pathogens including Enterobacteriaceae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. The expressions of metallo-β-lactamases such as inosine 5'-monophosphate (IMP), Verona integron-mediated metallo-β-lactamase (VIM), and New Delhi metallo-β-lactamase (NDM) are associated with a higher resistance rate of CFDC. Carbapenem-resistant phenotype has little effect on the resistance rate, although the acquisition of a particular carbapenemase may affect the susceptibility of the pathogens to CFDC. For potential resistance mechanism, mutations in β-lactamases and TonB-dependent receptors, which assist CFDC entering bacteria, would increase a minimum inhibitory concentration (MIC)90 value of CFDC against MDR pathogens. Since the development of CFDC, resistance during its utilization has been reported thus, prudent clinical applications are still necessary to preserve the activity of CFDC.

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In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects

Bianco

Boattini

Comini

et al. 2021

Eur J Clin Microbiol Infect Dis

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In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects --Manuscript Draft--Manuscript Number: EJCM-D-21-00999R2 Full Title: In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects Article Type:

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Clinical Evolution of AmpC-Mediated Ceftazidime-Avibactam and Cefiderocol Resistance in Enterobacter cloacae Complex Following Exposure to Cefepime

Cited by 63 publications

References 15 publications

Cefiderocol Activity Against ClinicalPseudomonas aeruginosaIsolates Exhibiting Ceftolozane-Tazobactam Resistance

Cefiderocol Activity Against ClinicalPseudomonas aeruginosaIsolates Exhibiting Ceftolozane-Tazobactam Resistance

Cefiderocol: An Overview of Its in-vitro and in-vivo Activity and Underlying Resistant Mechanisms

In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects

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