-
A 46-week outbreak of ertapenem-resistant, non-carbapenemase encoding Klebsiella pneumoniae ST45 in a paediatric cardiac unit involving shared equipment, United Kingdom, April 2022 to February 2023
-
Alice J Fraser1
,
Christopher M Parry2,3
,
Beatriz Larru4
,
Lindsay Case4
,
Kate Ball2
,
Caitlin Duggan1
,
Thomas Edwards1,*
,
Eva Heinz3,5,6,*
-
View Affiliations Hide AffiliationsAffiliations: 1 Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom 2 Department of Microbiology, Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom 3 Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom 4 Department of Infection Prevention and Control, Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom 5 Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom 6 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom* These authors contributed equally to this work and share last authorship.Correspondence:Eva Heinzeva.heinz strath.ac.uk
-
View Citation Hide Citation
Citation style for this article: Fraser Alice J, Parry Christopher M, Larru Beatriz, Case Lindsay, Ball Kate, Duggan Caitlin, Edwards Thomas, Heinz Eva. A 46-week outbreak of ertapenem-resistant, non-carbapenemase encoding Klebsiella pneumoniae ST45 in a paediatric cardiac unit involving shared equipment, United Kingdom, April 2022 to February 2023. Euro Surveill. 2025;30(43):pii=2500133. https://doi.org/10.2807/1560-7917.ES.2025.30.43.2500133 Received: 21 Feb 2025; Accepted: 27 Jun 2025
Abstract
An outbreak of an ertapenem-resistant Klebsiella pneumoniae clone occurred in a specialist children’s hospital in Liverpool, United Kingdom (UK), from April 2022 to February 2023. Carbapenem-resistant K. pneumoniae is unusual in the UK, and identification of two isolates exhibiting ertapenem resistance in the same ward in December 2022 raised concerns and triggered an outbreak investigation. Potential transmission through shared equipment was identified; a total of 11 patients were colonised and/or infected by phenotypically similar isolates. Multilocus sequence typing supported hospital transmission, and short-read whole genome sequencing (WGS) was performed on all isolates; long-read sequencing was conducted for three isolates to confidently resolve the plasmid structure. WGS confirmed a clonal outbreak and strongly supported the suspected nosocomial transmission. Detailed analysis of the resistance determinants indicated that ertapenem resistance was driven by a combination of different beta-lactamases, which would not alone convey this resistance profile, along with modifications in porin structure that suggested a synergistic interaction. These findings highlight how highly resistant strains could be mislabelled as predicted sensitive when considering genetic determinants in isolation and underscore the need to study beta-lactam resistances beyond the presence or absence of specific genes but also to consider co-occurrence.
Article metrics loading...
Full text loading...
References
-
Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80(3):629-61. https://doi.org/10.1128/MMBR.00078-15 PMID: 27307579
-
Cassini A, Högberg LD, Plachouras D, Quattrocchi A, Hoxha A, Simonsen GS, et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis. 2019;19(1):56-66. https://doi.org/10.1016/S1473-3099(18)30605-4 PMID: 30409683
-
Mestrovic T, Aguilar GR, Swetschinski LR, Ikuta KS, Gray AP, Weaver ND, et al. The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis. Lancet Public Health. 2022;7(11):e897-913. https://doi.org/10.1016/S2468-2667(22)00225-0 PMID: 36244350
-
Ling W, Furuya-Kanamori L, Ezure Y, Harris PNA, Paterson DL. Adverse clinical outcomes associated with infections by Enterobacterales producing ESBL (ESBL-E): a systematic review and meta-analysis. JAC Antimicrob Resist. 2021;3(2):dlab068. https://doi.org/10.1093/jacamr/dlab068 PMID: 35233528
-
Xu L, Sun X, Ma X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae. Ann Clin Microbiol Antimicrob. 2017;16(1):18. https://doi.org/10.1186/s12941-017-0191-3 PMID: 28356109
-
Nelson RE, Hatfield KM, Wolford H, Samore MH, Scott RD 2nd, Reddy SC, et al. National estimates of healthcare costs associated with multidrug-resistant bacterial infections among hospitalized patients in the United States. Clin Infect Dis. 2021;72(Suppl 1):S17-26. https://doi.org/10.1093/cid/ciaa1581 PMID: 33512523
-
Palmieri M, Wyres KL, Mirande C, Qiang Z, Liyan Y, Gang C, et al. Genomic evolution and local epidemiology of Klebsiella pneumoniae from a major hospital in Beijing, China, over a 15 year period: dissemination of known and novel high-risk clones. Microb Genom. 2019;7(6):000520. PMID: 33629946
-
Changruenngam S, Modchang C, Bicout DJ. Modelling of the transmission dynamics of carbapenem-resistant Klebsiella pneumoniae in hospitals and design of control strategies. Sci Rep. 2022;12(1):3805. https://doi.org/10.1038/s41598-022-07728-w PMID: 35264643
-
Moran RA, Baomo L, Doughty EL, Guo Y, Ba X, van Schaik W, et al. Extended-spectrum β-lactamase genes traverse the Escherichia coli populations of intensive care unit patients, staff, and environment. Microbiol Spectr. 2023;11(2):e0507422. https://doi.org/10.1128/spectrum.05074-22 PMID: 36916926
-
Gorrie CL, Mirčeta M, Wick RR, Judd LM, Lam MMC, Gomi R, et al. Genomic dissection of Klebsiella pneumoniae infections in hospital patients reveals insights into an opportunistic pathogen. Nat Commun. 2022;13(1):3017. https://doi.org/10.1038/s41467-022-30717-6 PMID: 35641522
-
Rosas NC, Wilksch J, Barber J, Li J, Wang Y, Sun Z, et al. The evolutionary mechanism of non-carbapenemase carbapenem-resistant phenotypes in Klebsiella spp. eLife. 2023;12:e83107. https://doi.org/10.7554/eLife.83107 PMID: 37410078
-
Holt KE, Wertheim H, Zadoks RN, Baker S, Whitehouse CA, Dance D, et al. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci USA. 2015;112(27):E3574-81. https://doi.org/10.1073/pnas.1501049112 PMID: 26100894
-
The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Guidance document on broth microdilution testing of cefiderocol. Växjö: EUCAST; 2020. Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Guidance_documents/Cefiderocol_MIC_testing_EUCAST_guidance_document_201217.pdf
-
Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-Hinton broth. Diagn Microbiol Infect Dis. 2019;94(4):321-5. https://doi.org/10.1016/j.diagmicrobio.2019.03.003 PMID: 31029489
-
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114-20. https://doi.org/10.1093/bioinformatics/btu170 PMID: 24695404
-
Seemann T. Shovill: Faster SPAdes Assembly of Illumina Reads (v1. 1.0). 2018. Available from: https://github.com/kristyhoran/shovill-1
-
Oxford Nanopore Technologies. Guppy. Available from: https://communitynanoporetechcom/downloads
-
Wick RR, Menzel P. Filtlong. 2017. Available from: https://github com/rrwick/Filtlong
-
Wick R. Porechop: adapter trimmer for Oxford Nanopore reads. 2018. Available from: https://github com/rrwick/Porechop
-
Kolmogorov M, Yuan J, Lin Y, Pevzner PA. Assembly of long, error-prone reads using repeat graphs. Nat Biotechnol. 2019;37(5):540-6. https://doi.org/10.1038/s41587-019-0072-8 PMID: 30936562
-
Wick RR, Schultz MB, Zobel J, Holt KE. Bandage: interactive visualization of de novo genome assemblies. Bioinformatics. 2015;31(20):3350-2. https://doi.org/10.1093/bioinformatics/btv383 PMID: 26099265
-
-
Wick RR, Holt KE. Polypolish: Short-read polishing of long-read bacterial genome assemblies. PLOS Comput Biol. 2022;18(1):e1009802. https://doi.org/10.1371/journal.pcbi.1009802 PMID: 35073327
-
Bouras G, Judd LM, Edwards RA, Vreugde S, Stinear TP, Wick RR. How low can you go? Short-read polishing of Oxford Nanopore bacterial genome assemblies. Microb Genom. 2024;10(6):001254. https://doi.org/10.1099/mgen.0.001254 PMID: 38833287
-
Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv arXiv:13033997. 2013. Available from: https://arxiv.org/abs/1303.3997
-
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078-9.
-
Rutherford K, Parkhill J, Crook J, Horsnell T, Rice P, Rajandream M-A, et al. Artemis: sequence visualization and annotation. Bioinformatics. 2000;16(10):944-5. https://doi.org/10.1093/bioinformatics/16.10.944 PMID: 11120685
-
Lam MMC, Wick RR, Watts SC, Cerdeira LT, Wyres KL, Holt KE. A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex. Nat Commun. 2021;12(1):4188. https://doi.org/10.1038/s41467-021-24448-3 PMID: 34234121
-
Hunt M, Mather AE, Sánchez-Busó L, Page AJ, Parkhill J, Keane JA, et al. ARIBA: rapid antimicrobial resistance genotyping directly from sequencing reads. Microb Genom. 2017;3(10):e000131. https://doi.org/10.1099/mgen.0.000131 PMID: 29177089
-
Alcock BP, Huynh W, Chalil R, Smith KW, Raphenya AR, Wlodarski MA, et al. CARD 2023: expanded curation, support for machine learning, and resistome prediction at the Comprehensive Antibiotic Resistance Database. Nucleic Acids Res. 2023;51(D1):D690-9. https://doi.org/10.1093/nar/gkac920 PMID: 36263822
-
Grant JR, Enns E, Marinier E, Mandal A, Herman EK, Chen CY, et al. Proksee: in-depth characterization and visualization of bacterial genomes. Nucleic Acids Res. 2023;51(W1):W484-92. https://doi.org/10.1093/nar/gkad326 PMID: 37140037
-
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(3):403-10. https://doi.org/10.1016/S0022-2836(05)80360-2 PMID: 2231712
-
Seemann T. Snippy: fast bacterial variant calling from NGS reads 2015. Available from: https://github.com//tseeman/snippy
-
Croucher NJ, Page AJ, Connor TR, Delaney AJ, Keane JA, Bentley SD, et al. Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins. Nucleic Acids Res. 2015;43(3):e15.
-
Page AJ, Taylor B, Delaney AJ, Soares J, Seemann T, Keane JA, et al. SNP-sites: rapid efficient extraction of SNPs from multi-FASTA alignments. Microb Genom. 2016;2(4):e000056. https://doi.org/10.1099/mgen.0.000056 PMID: 28348851
-
Price MN, Dehal PS, Arkin AP. FastTree 2--approximately maximum-likelihood trees for large alignments. PLoS One. 2010;5(3):e9490. https://doi.org/10.1371/journal.pone.0009490 PMID: 20224823
-
Pupko T, Pe’er I, Shamir R, Graur D. A fast algorithm for joint reconstruction of ancestral amino acid sequences. Mol Biol Evol. 2000;17(6):890-6. https://doi.org/10.1093/oxfordjournals.molbev.a026369 PMID: 10833195
-
Revell LJ. phytools 2.0: an updated R ecosystem for phylogenetic comparative methods (and other things). PeerJ. 2024;12:e16505. https://doi.org/10.7717/peerj.16505 PMID: 38192598
-
Wailan AM, Coll F, Heinz E, Tonkin-Hill G, Corander J, Feasey NA, et al. rPinecone: Define sub-lineages of a clonal expansion via a phylogenetic tree. Microb Genom. 2019;5(4):e000264. https://doi.org/10.1099/mgen.0.000264 PMID: 30920366
-
Letunic I, Bork P. Interactive Tree Of Life (iTOL): an online tool for phylogenetic tree display and annotation. Bioinformatics. 2007;23(1):127-8. https://doi.org/10.1093/bioinformatics/btl529 PMID: 17050570
-
Ruan Y, Li M, Wang D, Duan J, Zhang H, Zhou Y. Characteristics of non-carbapenemase producing carbapenem-resistant Klebsiella pneumoniae from a tertiary hospital in China. J Infect Dev Ctries. 2024;18(1):106-15. https://doi.org/10.3855/jidc.17779 PMID: 38377097
-
Schneiders T, Amyes SG, Levy SB. Role of AcrR and ramA in fluoroquinolone resistance in clinical Klebsiella pneumoniae isolates from Singapore. Antimicrob Agents Chemother. 2003;47(9):2831-7. https://doi.org/10.1128/AAC.47.9.2831-2837.2003 PMID: 12936981
-
Shi Q, Zhao J, Wei L, Zhu F, Ji J, Meng Y, et al. Transmission of ST45 and ST2407 extended-spectrum β-lactamase-producing Klebsiella pneumoniae in neonatal intensive care units, associated with contaminated environments. J Glob Antimicrob Resist. 2022;31:309-15. https://doi.org/10.1016/j.jgar.2022.10.006 PMID: 36265800
-
Cheong HS, Chung DR, Lee C, Kim SH, Kang C-I, Peck KR, et al. Emergence of serotype K1 Klebsiella pneumoniae ST23 strains co-producing the plasmid-mediated AmpC beta-lactamase DHA-1 and an extended-spectrum beta-lactamase in Korea. Antimicrob Resist Infect Control. 2016;5(1):50. https://doi.org/10.1186/s13756-016-0151-2 PMID: 27933141
-
Cuzon G, Naas T, Guibert M, Nordmann P. In vivo selection of imipenem-resistant Klebsiella pneumoniae producing extended-spectrum β-lactamase CTX-M-15 and plasmid-encoded DHA-1 cephalosporinase. Int J Antimicrob Agents. 2010;35(3):265-8. https://doi.org/10.1016/j.ijantimicag.2009.10.021 PMID: 20034767
-
Shin SY, Bae IK, Kim J, Jeong SH, Yong D, Kim JM, et al. Resistance to carbapenems in sequence type 11 Klebsiella pneumoniae is related to DHA-1 and loss of OmpK35 and/or OmpK36. J Med Microbiol. 2012;61(Pt 2):239-45. https://doi.org/10.1099/jmm.0.037036-0 PMID: 21940650
-
Barnaud G, Arlet G, Verdet C, Gaillot O, Lagrange PH, Philippon A. Salmonella enteritidis: AmpC plasmid-mediated inducible β-lactamase (DHA-1) with an ampR gene from Morganella morganii. Antimicrob Agents Chemother. 1998;42(9):2352-8. https://doi.org/10.1128/AAC.42.9.2352 PMID: 9736562
-
Chirabhundhu N, Luk-In S, Phuadraksa T, Wichit S, Chatsuwan T, Wannigama DL, et al. Occurrence and mechanisms of tigecycline resistance in carbapenem- and colistin-resistant Klebsiella pneumoniae in Thailand. Sci Rep. 2024;14(1):5215. https://doi.org/10.1038/s41598-024-55705-2 PMID: 38433246
-
Park S, Jin Y, Ko KS. Cross-resistance between tigecycline and cephalosporins regulated by expression of ompK35 and ompK36 in Klebsiella pneumoniae. Microb Pathog. 2025;205:107722. https://doi.org/10.1016/j.micpath.2025.107722 PMID: 40398640
-
National Institute for Health Care Excellence (NICE). British National Formulary Treatment Summaries: tigecycline. London: BMJ Publishing Group Ltd and the Royal Pharmaceutical Society of Great Britain; 2025. Available from: https://bnf.nice.org.uk/drugs/tigecycline
-
Iosifidis E, Violaki A, Michalopoulou E, Volakli E, Diamanti E, Koliouskas D, et al. Use of tigecycline in pediatric patients with infections predominantly due to extensively drug-resistant gram-negative bacteria. J Pediatric Infect Dis Soc. 2017;6(2):123-8. PMID: 27000866
-
Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies. J Antimicrob Chemother. 2008;62(5):895-904. https://doi.org/10.1093/jac/dkn311 PMID: 18676620
-
He S, Hickman AB, Varani AM, Siguier P, Chandler M, Dekker JP, et al. Insertion sequence IS 26 reorganizes plasmids in clinically isolated multidrug-resistant bacteria by replicative transposition. MBio. 2015;6(3):00762-15. https://doi.org/10.1128/mBio.00762-15 PMID: 26060276
-
Che Y, Yang Y, Xu X, Břinda K, Polz MF, Hanage WP, et al. Conjugative plasmids interact with insertion sequences to shape the horizontal transfer of antimicrobial resistance genes. Proc Natl Acad Sci USA. 2021;118(6):e2008731118. https://doi.org/10.1073/pnas.2008731118 PMID: 33526659
Data & Media loading...
Supplementary data
-
-
Supplement
-

