Rapid Development of Cefiderocol Resistance in Carbapenem-resistant <i>Enterobacter cloacae</i> During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor <i>cirA</i>

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Abstract

We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

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In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria

Akinobu Ito, Takafumi Sato, Merime Ota … (2017)

ABSTRACT Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.

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In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-nonsusceptible Gram-negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-2014 Study)

Krystyna Kazmierczak, Masakatsu Tsuji, Mark Wise … (2018)

Cefiderocol is a siderophore cephalosporin in development for treatment of infections caused by Gram-negative bacilli, including carbapenem-resistant and multidrug-resistant isolates. β-Lactamase carriage and in vitro activity of cefiderocol were determined against 1272 meropenem-non-susceptible isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii collected as part of the SIDERO-WT-2014 surveillance study. Minimum inhibitory concentration (MIC) values for cefiderocol were ≤4 µg/mL against 97.7% of tested isolates, including 100% of IMP-positive (range, 1-2 µg/mL), OXA-58-positive (MIC90, 1 µg/mL), KPC-positive (MIC90, 2 µg/mL), VIM-positive (MIC90, 2 µg/mL), and OXA-48-like-positive (MIC90, 4 µg/mL) isolates; 99.3% of carbapenemase-negative isolates (MIC90, 1 µg/mL); 97.2% of OXA-23-positive isolates (MIC90, 1 µg/mL); 95.2% of OXA-24-positive isolates (MIC90, 1 µg/mL); 91.7% of GES-positive isolates (MIC90, 4 µg/mL); and 64.3% of NDM-positive isolates (MIC90, 8 µg/mL). A total of 29 isolates (2.3%; 15 OXA-23-producers, 6 OXA-24-producers, 5 NDM-producers, and 3 carbapenemase-negative isolates) exhibited cefiderocol MIC ≥8 µg/mL, confirming there was no clear correlation between carriage of β-lactamases included in the molecular testing algorithm and elevated cefiderocol MICs. Similarly, no correlation was observed between cefiderocol MICs and truncation or loss of porin proteins in meropenem-non-susceptible isolates of E. coli and K. pneumoniae. Cefiderocol MICs were also ≤4 µg/mL against 99.3% of 136 colistin-resistant Enterobacteriaceae collected as part of the SIDERO-WT-2014 study, including isolates carrying mcr-1 (MIC90, 2 µg/mL). Cefiderocol demonstrated potent in vitro activity against a collection of carbapenemase-producing and carbapenemase-negative meropenem-non-susceptible Gram-negative bacilli for which few treatment options are available, including the majority of metallo-β-lactamase producing isolates identified.

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Carbapenem-resistant Enterobacteriaceae in the community: a scoping review.

Ana M. Kelly, Barun Mathema, Elaine L. Larson (2017)

Carbapenem antibiotics are used as a last resort to treat serious Gram-negative bacteria (GNB) infections; however, carbapenemase-producing strains of GNB have emerged as a major source of resistance. Owing to the highly transmissible nature of plasmid-borne carbapenemases, numerous reports have warned about the likely spread into the community from healthcare settings. Since the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the community is largely unknown, we conducted a scoping review of the literature to assess the percentage of CRE isolates that could be associated with the community. Initially, 361 studies were assessed and 15 met the inclusion criteria. Although 5 studies (33.3%) found no community-associated CRE, the remaining 10 studies identified percentages ranging from 0.04% to 29.5% of either community-associated or community-onset CRE among their samples, with US-based studies alone ranging from 5.6 to 10.8%. The presence of CRE in the community poses an urgent public health threat.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Infect Dis

Journal ID (iso-abbrev): Clin Infect Dis

Journal ID (publisher-id): cid

Title: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

Publisher: Oxford University Press (US )

ISSN (Print): 1058-4838

ISSN (Electronic): 1537-6591

Publication date Collection: 01 March 2022

Publication date (Electronic): 03 June 2021

Publication date PMC-release: 03 June 2021

Volume: 74

Issue: 5

Pages: 905-908

Affiliations

[1 ] Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital , Heidelberg,Germany

[2 ] Department of Anesthesiology, Heidelberg University Hospital , Heidelberg,Germany

[3 ] Pharmacy Department, Heidelberg University Hospital , Heidelberg, Germany

[4 ] Department of Internal Medicine IV, Heidelberg University Hospital , Heidelberg, Germany

[5 ] Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital , Heidelberg, Germany

Author notes

S. K. and S. B. contributed equally to this work.

Correspondence: D. Nurjadi, Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany ( dennis.nurjadi@ 123456uni-heidelberg.de ).

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Dennis Nurjadi https://orcid.org/0000-0002-1278-5939

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Publisher ID: ciab511

DOI: 10.1093/cid/ciab511

PMC ID: 8906715

PubMed ID: 34079986

SO-VID: f0041854-fb94-4f75-87ec-46f0faf06f82

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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Date received : 09 March 2021

Date: 25 May 2021

Date: 16 July 2021

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Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA

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Most cited references 14

In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria

In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-nonsusceptible Gram-negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-2014 Study)

Carbapenem-resistant Enterobacteriaceae in the community: a scoping review.

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