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Abstract

Resistance to piperacillin/tazobactam (TZP) in has predominantly been associated with mechanisms that confer resistance to third-generation cephalosporins. Recent reports have identified strains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third-generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype in (=58) isolated between 2014–2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasive isolates (=1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype (=68), and piperacillin/tazobactam and third-generation cephalosporin-susceptible (TZP-S/3GC-S, =1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types, which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasive isolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor-resistant β-lactamases, and an S133G mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Eleven (19%) of the isolates had no putative mechanism identified from the genomic data. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.

Funding
This study was supported by the:
  • Liverpool School of Tropical Medicine (Award Directors Catalyst Fund)
    • Principle Award Recipient: AlasdairT M Hubbard
  • Liverpool School of Tropical Medicine (Award Directors Catalyst Fund)
    • Principle Award Recipient: ThomasEdwards
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2022-04-11
2022-05-18
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References

  1. Laupland KB. Incidence of bloodstream infection: a review of population-based studies. Clin Microbiol Infect 2013; 19:492–500 [View Article] [PubMed]
    [Google Scholar]
  2. Bonten M, Johnson JR, van den Biggelaar AHJ, Georgalis L, Geurtsen J et al. Epidemiology of Escherichia coli bacteremia: a systematic literature review. Clin Infect Dis 2021; 72:1211–1219 [View Article] [PubMed]
    [Google Scholar]
  3. Public Health England Laboratory surveillance of Escherichia coli bacteraemia in England, Wales and Northern Ireland. Health Protection Report 2018; 13:37
    [Google Scholar]
  4. World Health Organization Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics; 2017
  5. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18:318–327 [View Article] [PubMed]
    [Google Scholar]
  6. World Health Organization Landscape of diagnostics against antibacterial resistance, gaps and priorities; 2019
  7. Temkin E, Fallach N, Almagor J, Gladstone BP, Tacconelli E et al. Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study. Lancet Glob Health 2018; 6:e969–e979 [View Article] [PubMed]
    [Google Scholar]
  8. European Centre for Disease Prevention and Control Surveillance of antimicrobial resistance in Europe; 2018
  9. Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA et al. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J Mol Biol 2019; 431:3472–3500 [View Article] [PubMed]
    [Google Scholar]
  10. Gin A, Dilay L, Karlowsky JA, Walkty A, Rubinstein E et al. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev Anti Infect Ther 2007; 5:365–383 [View Article] [PubMed]
    [Google Scholar]
  11. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev 2010; 23:160–201 [View Article] [PubMed]
    [Google Scholar]
  12. Johnson DM, Biedenbach DJ, Jones RN. Potency and antimicrobial spectrum update for piperacillin/tazobactam (2000): emphasis on its activity against resistant organism populations and generally untested species causing community-acquired respiratory tract infections. Diagn Microbiol Infect Dis 2002; 43:49–60 [View Article] [PubMed]
    [Google Scholar]
  13. Kim M-K, Xuan D, Quintiliani R, Nightingale CH, Nicolau DP. Pharmacokinetic and pharmacodynamic profile of high dose extended interval piperacillin-tazobactam. J Antimicrob Chemother 2001; 48:259–267 [View Article] [PubMed]
    [Google Scholar]
  14. Barton GJ, Morecroft CW, Henney NC. A survey of antibiotic administration practices involving patients with sepsis in UK critical care units. Int J Clin Pharm 2020; 42:65–71 [View Article] [PubMed]
    [Google Scholar]
  15. Wilson APR. Sparing carbapenem usage. J Antimicrob Chemother 2017; 72:2410–2417 [View Article] [PubMed]
    [Google Scholar]
  16. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2015; 2:ofv050 [View Article] [PubMed]
    [Google Scholar]
  17. Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320:984–994 [View Article] [PubMed]
    [Google Scholar]
  18. Gutiérrez-Gutiérrez B, Rodríguez-Baño J. Current options for the treatment of infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae in different groups of patients. Clinical Microbiology and Infection 2019; 25:932–942 [View Article]
    [Google Scholar]
  19. van Duin D, Bonomo RA. Ceftazidime/avibactam and ceftolozane/tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 2016; 63:234–241 [View Article] [PubMed]
    [Google Scholar]
  20. Lee J, Oh CE, Choi EH, Lee HJ. The impact of the increased use of piperacillin/tazobactam on the selection of antibiotic resistance among invasive Escherichia coli and Klebsiella pneumoniae isolates. Int J Infect Dis 2013; 17:e638–43 [View Article] [PubMed]
    [Google Scholar]
  21. Suzuki Y, Sato T, Fukushima Y, Nakajima C, Suzuki Y et al. Contribution of β-lactamase and efflux pump overproduction to tazobactam-piperacillin resistance in clinical isolates of Escherichia coli. Int J Antimicrob Agents 2020; 55:105919 [View Article] [PubMed]
    [Google Scholar]
  22. Schechter LM, Creely DP, Garner CD, Shortridge D, Nguyen H et al. Extensive gene amplification as a mechanism for piperacillin-tazobactam resistance in Escherichia coli. mBio 2018; 9:e00583-18 [View Article] [PubMed]
    [Google Scholar]
  23. Rodríguez-Villodres Á, Gil-Marqués ML, Álvarez-Marín R, Bonnin RA, Pachón-Ibáñez ME et al. Extended-spectrum resistance to β-lactams/β-lactamase inhibitors (ESRI) evolved from low-level resistant Escherichia coli. J Antimicrob Chemother 2020; 75:77–85 [View Article] [PubMed]
    [Google Scholar]
  24. Abdelraouf K, Chavda KD, Satlin MJ, Jenkins SG, Kreiswirth BN et al. Piperacillin-tazobactam-resistant/third-generation cephalosporin-susceptible Escherichia coli and Klebsiella pneumoniae isolates: resistance mechanisms and in vitro-in vivo discordance. Int J Antimicrob Agents 2020; 55:105885 [View Article] [PubMed]
    [Google Scholar]
  25. Zhou K, Tao Y, Han L, Ni Y, Sun J. Piperacillin-Tazobactam (TZP) resistance in Escherichia coli due to hyperproduction of TEM-1 β-lactamase mediated by the promoter Pa/Pb. Front Microbiol 2019; 10:833 [View Article]
    [Google Scholar]
  26. Hubbard ATM, Mason J, Roberts P, Parry CM, Corless C et al. Piperacillin/tazobactam resistance in a clinical isolate of Escherichia coli due to IS26-mediated amplification of blaTEM-1B. Nat Commun 2020; 11:4915 [View Article] [PubMed]
    [Google Scholar]
  27. Hansen KH, Andreasen MR, Pedersen MS, Westh H, Jelsbak L et al. Resistance to piperacillin/tazobactam in Escherichia coli resulting from extensive IS26-associated gene amplification of blaTEM-1. J Antimicrob Chemother 2019; 74:3179–3183 [View Article] [PubMed]
    [Google Scholar]
  28. Rosenkilde CEH, Munck C, Porse A, Linkevicius M, Andersson DI et al. Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase. Nat Commun 2019; 10:618 [View Article] [PubMed]
    [Google Scholar]
  29. Andrews JM, Howe RA. BSAC Working Party on Susceptibility Testing BSAC standardized disc susceptibility testing method (version 10). J Antimicrob Chemother 2011; 66:2726–2757 [View Article] [PubMed]
    [Google Scholar]
  30. The European Committee on Antimicrobial Susceptibility Testing Breakpoint tables for interpretation of MICs and zone diameters. Version 10.0; 2020 http://www.eucast.org
  31. García-Fernández S, Bala Y, Armstrong T, García-Castillo M, Burnham CA et al. Multicenter evaluation of the new etest gradient diffusion method for piperacillin-tazobactam susceptibility testing of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex. J Clin Microbiol 2020; 58:e01042-19 [View Article] [PubMed]
    [Google Scholar]
  32. Bankevich A, Nurk S, Antipov D, Gurevich AA, Dvorkin M et al. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol 2012; 19:455–477 [View Article] [PubMed]
    [Google Scholar]
  33. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article] [PubMed]
    [Google Scholar]
  34. Hunt M, Mather AE, Sánchez-Busó L, Page AJ, Parkhill J et al. ARIBA: rapid antimicrobial resistance genotyping directly from sequencing reads. Microb Genom 2017; 3:10 [View Article] [PubMed]
    [Google Scholar]
  35. Inouye M, Dashnow H, Raven L-A, Schultz MB, Pope BJ et al. SRST2: Rapid genomic surveillance for public health and hospital microbiology labs. Genome Med 2014; 6:11 [View Article] [PubMed]
    [Google Scholar]
  36. Larsen MV, Cosentino S, Rasmussen S, Friis C, Hasman H et al. Multilocus sequence typing of total-genome-sequenced bacteria. J Clin Microbiol 2012; 50:1355–1361 [View Article] [PubMed]
    [Google Scholar]
  37. Carattoli A, Zankari E, García-Fernández A, Voldby Larsen M, Lund O et al. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother 2014; 58:3895–3903 [View Article]
    [Google Scholar]
  38. Page AJ, Cummins CA, Hunt M, Wong VK, Reuter S et al. Roary: rapid large-scale prokaryote pan genome analysis. Bioinformatics 2015; 31:3691–3693 [View Article] [PubMed]
    [Google Scholar]
  39. Page AJ, Taylor B, Delaney AJ, Soares J, Seemann T et al. SNP-sites: rapid efficient extraction of SNPs from multi-FASTA alignments. Microb Genom 2016; 2:e000056 [View Article] [PubMed]
    [Google Scholar]
  40. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol 2015; 32:268–274 [View Article] [PubMed]
    [Google Scholar]
  41. Letunic I, Bork P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res 2016; 44:W242–5 [View Article] [PubMed]
    [Google Scholar]
  42. Croucher NJ, Page AJ, Connor TR, Delaney AJ, Keane JA et al. Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins. Nucleic Acids Res 2015; 43:e15 [View Article] [PubMed]
    [Google Scholar]
  43. Kallonen T, Brodrick HJ, Harris SR, Corander J, Brown NM et al. Systematic longitudinal survey of invasive Escherichia coli in England demonstrates a stable population structure only transiently disturbed by the emergence of ST131. Genome Res 2017; 27:1437–1449 [View Article] [PubMed]
    [Google Scholar]
  44. Peter-Getzlaff S, Polsfuss S, Poledica M, Hombach M, Giger J et al. Detection of AmpC beta-lactamase in Escherichia coli: comparison of three phenotypic confirmation assays and genetic analysis. J Clin Microbiol 2011; 49:2924–2932 [View Article] [PubMed]
    [Google Scholar]
  45. McNally A, Kallonen T, Connor C, Abudahab K, Aanensen DM et al. Diversification of colonization factors in a multidrug-resistant Escherichia coli lineage evolving under negative frequency-dependent selection. mBio 2019; 10:e00644-19 [View Article] [PubMed]
    [Google Scholar]
  46. Whitmer GR, Moorthy G, Arshad M. The pandemic Escherichia coli sequence type 131 strain is acquired even in the absence of antibiotic exposure. PLOS Pathog 2019; 15:e1008162 [View Article] [PubMed]
    [Google Scholar]
  47. Cunha MPV, Saidenberg AB, Moreno AM, Ferreira AJP, Vieira MAM et al. Pandemic extra-intestinal pathogenic Escherichia coli (ExPEC) clonal group O6-B2-ST73 as a cause of avian colibacillosis in Brazil. PLOS ONE 2017; 12:e0178970 [View Article] [PubMed]
    [Google Scholar]
  48. Rothe K, Wantia N, Spinner CD, Schneider J, Lahmer T et al. Antimicrobial resistance of bacteraemia in the emergency department of a German university hospital (2013-2018): potential carbapenem-sparing empiric treatment options in light of the new EUCAST recommendations. BMC Infect Dis 2019; 19:1091 [View Article] [PubMed]
    [Google Scholar]
  49. Baker TM, Rogers W, Chavda KD, Westblade LF, Jenkins SG et al. Epidemiology of bloodstream infections caused by Escherichia coli and Klebsiella pneumoniae that are piperacillin-tazobactam-nonsusceptible but ceftriaxone-susceptible. Open Forum Infect Dis 2018; 5:ofy300 [View Article] [PubMed]
    [Google Scholar]
  50. Stainton SM, Monogue ML, Nicolau DP. In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains. Antimicrob Agents Chemother 2017; 61:e00491-17 [View Article] [PubMed]
    [Google Scholar]
  51. Carlisle L, Justo JA, Al-Hasan MN. Bloodstream infection due to piperacillin/tazobactam non-susceptible, cephalosporin-susceptible Escherichia coli: a missed opportunity for de-escalation of therapy. Antibiotics (Basel) 2018; 7:E104 [View Article] [PubMed]
    [Google Scholar]
  52. Robson SE, Cockburn A, Sneddon J, Mohana A, Bennie M et al. Optimizing carbapenem use through a national quality improvement programme. J Antimicrob Chemother 2018; 73:2223–2230 [View Article] [PubMed]
    [Google Scholar]
  53. Williams CT, Musicha P, Feasey NA, Adams ER, Edwards T. ChloS-HRM, a novel assay to identify chloramphenicol-susceptible Escherichia coli and Klebsiella pneumoniae in Malawi. J Antimicrob Chemother 2019; 74:1212–1217 [View Article] [PubMed]
    [Google Scholar]
  54. Charalampous T, Kay GL, Richardson H, Aydin A, Baldan R et al. Nanopore metagenomics enables rapid clinical diagnosis of bacterial lower respiratory infection. Nat Biotechnol 2019; 37:783–792 [View Article] [PubMed]
    [Google Scholar]
  55. Harmer CJ, Pong CH, Hall RM. Structures bounded by directly-oriented members of the IS26 family are pseudo-compound transposons. Plasmid 2020; 111:102530 [View Article] [PubMed]
    [Google Scholar]
  56. Sirot D, Chanal C, Bonnet R, De Champs C, Bret L. Inhibitor-resistant TEM-33 beta-lactamase in a Shigella sonnei isolate. Antimicrob Agents Chemother 2001; 45:2179–2180 [View Article] [PubMed]
    [Google Scholar]
  57. Che T, Bethel CR, Pusztai-Carey M, Bonomo RA, Carey PR. The different inhibition mechanisms of OXA-1 and OXA-24 β-lactamases are determined by the stability of active site carboxylated lysine. J Biol Chem 2014; 289:6152–6164 [View Article] [PubMed]
    [Google Scholar]
  58. Livermore DM, Day M, Cleary P, Hopkins KL, Toleman MA et al. OXA-1 β-lactamase and non-susceptibility to penicillin/β-lactamase inhibitor combinations among ESBL-producing Escherichia coli. J Antimicrob Chemother 2019; 74:326–333 [View Article] [PubMed]
    [Google Scholar]
  59. Nielsen KL, Hansen KH, Nielsen JB, Knudsen JD, Schønning K et al. Mutational change of CTX-M-15 to CTX-M-127 resulting in mecillinam resistant Escherichia coli during pivmecillinam treatment of a patient. Microbiologyopen 2019; 8:e941 [View Article] [PubMed]
    [Google Scholar]
  60. Edwards T, Williams C, Teethaisong Y, Sealey J, Sasaki S et al. A highly multiplexed melt-curve assay for detecting the most prevalent carbapenemase, ESBL, and AmpC genes. Diagn Microbiol Infect Dis 2020; 97:115076 [View Article] [PubMed]
    [Google Scholar]
  61. Han MS, Park KS, Jeon JH, Lee JK, Lee JH et al. SHV hyperproduction as a mechanism for piperacillin-tazobactam resistance in extended-spectrum cephalosporin-susceptible Klebsiella pneumoniae. Microb Drug Resist 2020; 26:334–340 [View Article] [PubMed]
    [Google Scholar]
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