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<p>We investigated the genomic epidemiology of Ambler class C (AmpC-type) β-lactamases in <i>Enterobacter cloacae</i> complex and <i>Klebsiella aerogenes</i> in the national carbapenemase-producing Enterobacterales (CPE) surveillance of the Netherlands between 2012 and 2023. A total of 399 <i>E. cloacae</i> complex and <i>K. aerogenes</i> isolates from 399 patients were analyzed using whole-genome sequencing to assess genetic relatedness, resistance genes, porin, and AmpC-regulatory gene profiles, plasmid replicons, and the genomic location of AmpC-genes, respectively. Of the 399 patients, 217 were male (54%), and the median age was 67&#xa0;years. Carbapenemase production was assessed using the carbapenem inactivation method (CIM) and CarbaNP-test. A considerable proportion of <i>E. cloacae</i> complex (32%) and <i>K. aerogenes</i> (52%) isolates were CIM-positive in the absence of detectable carbapenemase genes (IMP, KPC, NDM, OXA-48-like, VIM) by the CarbaPCR, a phenotype termed CIM + Carba-. These isolates were mostly (81.9%) susceptible (EUCAST ≤ 2mg/L) to meropenem. The majority of CIM + Carba + isolates with major carbapenemase genes were gained from pre-emptive screening, while CIM + Carba- isolates were mainly taken for diagnostic purposes. Genomic analysis identified 18 genogroups, with <i>E. kobei</i>, <i>E. roggenkampii</i>, <i>E. ludwigii,</i> and <i>K. aerogenes</i> showing the CIM + Carba- phenotype, were mostly lacking porins and AmpC regulators, and correlated with chromosome-encoded AmpC-type β-lactamases like <i>bla</i><sub>ACT-28</sub>, <i>bla</i><sub>ACT-52,</sub> <i>bla</i><sub>MIR-3</sub>, <i>bla</i><sub>MIR-11</sub> or <i>ampC</i> of which the majority (63%) yielded a positive CarbaNP-test. These CIM + Carba- isolates carried only few plasmids, and there was limited evidence of nosocomial spread. CIM + Carba- <i>E. kobei</i> carrying <i>bla</i><sub>ACT-28</sub> overproduced ACT-28 protein in the CIM. Overall, the <i>Enterobacter</i> and <i>K. aerogenes</i> population in the Netherlands is genetically diverse, with most isolates carrying species-specific AmpC-type β-lactamases. Isolates with low MIC for meropenem that lack porins and major carbapenemases represent a low-risk for public health.</p>

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Ambler class C-type β-lactamases and porin alterations in Enterobacter cloacae complex and Klebsiella aerogenes in the Netherlands, 2012–2023

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  • 发表日期：

    2026年1月30日

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  • Elke van Gorp,
  • Simon Lansu,
  • Cornelia C. H. Wielders,
  • Angela de Haan,
  • Gert-Jan Godeke,
  • Sandra Witteveen,
  • Jeroen Bos,
  • Fabian Landman,
  • Maureen Ouw,
  • Herman F. Wunderink,
  • Maurits P. A. van Meer,
  • Wil van der Zwet,
  • Daan W. Notermans,
  • Antoni P. A. Hendrickx,
  • A. L. E. van Arkel,
  • M. A. Leversteijn-van Hall,
  • W. van den Bijllaardt,
  • R. van Mansfeld,
  • K. van Dijk,
  • B. Zwart,
  • B. M. W. Diederen,
  • H. Berkhout,
  • A. Ott,
  • K. Waar,
  • W. Ang,
  • J. da Silva,
  • A. L. M. Vlek,
  • J. J. J. M. Stohr,
  • L. G. M. Bode,
  • A. Jansz,
  • S. Paltansing,
  • A. J. van Griethuysen,
  • J. R. Lo Ten Foe,
  • M. J. C. A. van Trijp,
  • M. Wong,
  • A. E. Muller,
  • M. P. M. van der Linden,
  • M. van Rijn,
  • S. B. Debast,
  • E. Kolwijck,
  • N. Al Naiemi,
  • T. Schulin,
  • S. Dinant,
  • S. P. van Mens,
  • D. C. Melles,
  • J. W. T. Cohen Stuart,
  • P. Gruteke,
  • A. P. van Dam,
  • I. Maat,
  • B. Maraha,
  • J. C. Sinnige,
  • E. van der Vorm,
  • M. P. A. van Meer,
  • M. de Graaf,
  • E. de Jong,
  • S. J. Vainio,
  • E. Heikens,
  • M. den Reijer,
  • J. W. Dorigo-Zetsma,
  • A. Troelstra,
  • E. Bathoorn,
  • J. de Vries,
  • D. W. van Dam,
  • E. I. G. B. de Brauwer,
  • R. Steingrover,
  • F. Koene,
  • C. Oliveira dos Santos

摘要

We investigated the genomic epidemiology of Ambler class C (AmpC-type) β-lactamases in Enterobacter cloacae complex and Klebsiella aerogenes in the national carbapenemase-producing Enterobacterales (CPE) surveillance of the Netherlands between 2012 and 2023. A total of 399 E. cloacae complex and K. aerogenes isolates from 399 patients were analyzed using whole-genome sequencing to assess genetic relatedness, resistance genes, porin, and AmpC-regulatory gene profiles, plasmid replicons, and the genomic location of AmpC-genes, respectively. Of the 399 patients, 217 were male (54%), and the median age was 67 years. Carbapenemase production was assessed using the carbapenem inactivation method (CIM) and CarbaNP-test. A considerable proportion of E. cloacae complex (32%) and K. aerogenes (52%) isolates were CIM-positive in the absence of detectable carbapenemase genes (IMP, KPC, NDM, OXA-48-like, VIM) by the CarbaPCR, a phenotype termed CIM + Carba-. These isolates were mostly (81.9%) susceptible (EUCAST ≤ 2mg/L) to meropenem. The majority of CIM + Carba + isolates with major carbapenemase genes were gained from pre-emptive screening, while CIM + Carba- isolates were mainly taken for diagnostic purposes. Genomic analysis identified 18 genogroups, with E. kobei, E. roggenkampii, E. ludwigii, and K. aerogenes showing the CIM + Carba- phenotype, were mostly lacking porins and AmpC regulators, and correlated with chromosome-encoded AmpC-type β-lactamases like blaACT-28, blaACT-52, blaMIR-3, blaMIR-11 or ampC of which the majority (63%) yielded a positive CarbaNP-test. These CIM + Carba- isolates carried only few plasmids, and there was limited evidence of nosocomial spread. CIM + Carba- E. kobei carrying blaACT-28 overproduced ACT-28 protein in the CIM. Overall, the Enterobacter and K. aerogenes population in the Netherlands is genetically diverse, with most isolates carrying species-specific AmpC-type β-lactamases. Isolates with low MIC for meropenem that lack porins and major carbapenemases represent a low-risk for public health.