Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022

Coppi, Marco; Antonelli, Alberto; Niccolai, Claudia; Bartolini, A.; Bartolini, L.; Grazzini, Maddalena; Mantengoli, Elisabetta; Farese, Alberto; Pieralli, Filippo; Mechi, Maria Teresa; Pilato, Vincenzo Di; Giani, Tommaso; Rossolini, Gian María

doi:10.2807/1560-7917.es.2022.27.43.2200795

Cited by 33 publications

(12 citation statements)

References 15 publications

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“…Mutations in these genes are associated with cefiderocol resistance in the literature [ 18 , 19 , 20 ]. Several missense mutations were observed in a number of genes involved in iron uptake, such as fhu A, fep A, and iut A.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

et al. 2023

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Cefiderocol is a new siderophore cephalosporin that is effective against multidrug-resistant Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to evaluate the activity of this new antimicrobial agent against a collection of pathogens using broth microdilution assays and to analyze the possible mechanism of cefiderocol resistance in two resistant Klebsiella pneumoniae isolates. One hundred and ten isolates were tested, comprising 67 Enterobacterales, two Acinetobacter baumannii, one Achromobacter xylosoxidans, 33 Pseudomonas aeruginosa and seven Stenotrophomonas maltophilia. Cefiderocol showed good in vitro activity, with an MIC < 2 μg/mL, and was able to inhibit 94% of the tested isolates. We observed a resistance rate of 6%. The resistant isolates consisted of six Klebsiella pneumoniae and one Escherichia coli, leading to a resistance rate of 10.4% among the Enterobacterales. Whole-genome sequencing analysis was performed on two cefiderocol-resistant Klebsiella pneumoniae isolates to investigate the possible mutations responsible for the observed resistance. Both strains belonged to ST383 and harbored different resistant and virulence genes. The analysis of genes involved in iron uptake and transport showed the presence of different mutations located in fhuA, fepA, iutA, cirA, sitC, apbC, fepG, fepC, fetB, yicI, yicJ, and yicL. Furthermore, for the first time, to the best of our knowledge, we described two Klebsiella pneumoniae isolates that synthesize a truncated fecA protein due to the transition from G to A, leading to a premature stop codon in the amino acid position 569, and a TonB protein carrying a 4-amino acid insertion (PKPK) after Lysine 103. In conclusion, our data show that cefiderocol is an effective drug against multidrug-resistant Gram-negative bacteria. However, the higher resistance rate observed in Enterobacterales underlines the need for active surveillance to limit the spread of these pathogens and to avoid the risks associated with the emergence of resistance to new drugs.

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Section: Resultsmentioning

confidence: 99%

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

et al. 2023

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“…Our findings raise concern about a potential widespread NDM outbreak with subsequent establishment of endemicity, as noted due to healthcare-associated transmission across multiple institutions in Tuscany in 2018–2019. 5 , 35 – 37 …”

Section: Discussionmentioning

confidence: 99%

Genomic investigation of multispecies and multivariant bla_NDM outbreak reveals key role of horizontal plasmid transmission

Macesic,

Dennis,

Hawkey

et al. 2024

Infect. Control Hosp. Epidemiol.

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Objectives: New Delhi metallo-β-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel, but from 2019 we noted increasing incidence of NDM-positive clinical isolates. We investigated the clinical and genomic epidemiology of NDM carriage at a tertiary-care Australian hospital from 2016 to 2021. Methods: We identified 49 patients with 84 NDM-carrying isolates in an institutional database, and we collected clinical data from electronic medical record. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of blaNDM genes and to compare NDM plasmids. Results: Of 49 patients, 38 (78%) were identified in 2019–2021 and only 11 (29%) of 38 reported prior travel, compared with 9 (82%) of 11 in 2016–2018 (P = .037). In patients with NDM infection, the crude 7-day mortality rate was 0% and the 30-day mortality rate was 14% (2 of 14 patients). NDMs were noted in 41 bacterial strains (ie, species and sequence type combinations). Across 13 plasmid groups, 4 NDM variants were detected: blaNDM-1, blaNDM-4, blaNDM-5, and blaNDM-7. We noted a change from a diverse NDM plasmid repertoire in 2016–2018 to the emergence of conserved blaNDM-1 IncN and blaNDM-7 IncX3 epidemic plasmids, with interstrain spread in 2019–2021. These plasmids were noted in 19 (50%) of 38 patients and 35 (51%) of 68 genomes in 2019–2021. Conclusions: Increased NDM case numbers were due to local circulation of 2 epidemic plasmids with extensive interstrain transfer. Our findings underscore the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread.

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“…Moreover, a nosocomial outbreak of NDM-producing K. pneumoniae resistant to cefiderocol, mostly caused by a mutant clone with a cirA mutation, was recently reported. The resistant clone was able to spread in the absence of significant selective pressure by cefiderocol, suggesting that similar mutants do not necessarily exhibit a fitness defect [122]. Infection control to prevent outbreaks linked to such strains is essential to preserve the activity and utility of cefiderocol for the treatment of CRE infections [122,123].…”

Section: Cefiderocol Resistance Mechanisms In Enterobacterales: On-th...mentioning

confidence: 99%

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

et al. 2023

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Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections.Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine-and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases-the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections.

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Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022

Cited by 33 publications

References 15 publications

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

Genomic investigation of multispecies and multivariant bla_NDM outbreak reveals key role of horizontal plasmid transmission

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

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Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022

Cited by 33 publications

References 15 publications

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

In Vitro Activity of Cefiderocol on Multiresistant Bacterial Strains and Genomic Analysis of Two Cefiderocol Resistant Strains

Genomic investigation of multispecies and multivariant blaNDM outbreak reveals key role of horizontal plasmid transmission

Cefiderocol, a Siderophore Cephalosporin, as a Treatment Option for Infections Caused by Carbapenem-Resistant Enterobacterales

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Genomic investigation of multispecies and multivariant bla_NDM outbreak reveals key role of horizontal plasmid transmission