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Epidemiology and in vitro activity of ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam, eravacycline, plazomicin, and comparators against Greek carbapenemase-producing Klebsiella pneumoniae isolates

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A Correction to this article was published on 06 October 2022

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Abstract

Background

The increase in carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is of great concern because of limited treatment options. New antimicrobials were recently approved for clinical therapy. This study evaluated the epidemiology of carbapenemase-producing K. pneumoniae isolates collected at a Greek university hospital during 2017–2020, and their susceptibilities to ceftazidime–avibactam (CAZ/AVI), meropenem–vaborbactam (M/V), imipenem–relebactam (I/R), eravacycline, plazomicin, and comparators.

Methods

Minimum inhibitory concentrations (MICs) were evaluated by the MIC Test Strip method. Only colistin MICs were determined by the broth microdilution method. Carbapenemase genes were detected by PCR. Selected isolates were typed by multilocus sequence typing (MLST).

Results

A total of 266 carbapenemase-producing K. pneumoniae strains were isolated during the 4-year study period. Among them, KPC was the most prevalent (75.6%), followed by NDM (11.7%), VIM (5.6%), and OXA-48 (4.1%). KPC-producing isolates belonged mainly to ST258 and NDM producers belonged to ST11, whereas OXA-48- and VIM producers were polyclonal. Susceptibility to tigecycline, fosfomycin, and colistin was 80.5%, 83.8%, and 65.8%, respectively. Of the novel agents tested, plazomicin was the most active inhibiting 94% of the isolates at ≤ 1.5 μg/ml. CAZ/AVI and M/V inhibited all KPC producers and I/R 98.5% of them. All OXA-48 producers were susceptible to CAZ/AVI and plazomicin. The novel β-lactam/β-lactamase inhibitors (BLBLIs) tested were inactive against MBL-positive isolates, while eravacycline inhibited 61.3% and 66.7% of the NDM and VIM producers, respectively.

Conclusions

KPC remains the predominant carbapenemase among K. pneumoniae, followed by NDM. Novel BLBLIs, eravacycline, and plazomicin are promising agents for combating infections by carbapenemase-producing K. pneumoniae. However, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship.

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References

  1. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009;9:228–36.

    Article  CAS  Google Scholar 

  2. Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis. 2014;2:1170–5.

    Article  Google Scholar 

  3. Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis. 2017;215:S28–36.

    Article  CAS  Google Scholar 

  4. Hansen GT. Continuous evolution: perspective on the epidemiology of carbapenemase resistance among Enterobacterales and Other Gram-Negative Bacteria. Infect Dis Ther. 2021;10:75–92.

    Article  Google Scholar 

  5. Centers for Disease Control and Prevention (CDC) (2019) Antimicrobial resistance threats report. Available from: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed 5 Jan 2021

  6. World Health Organization (WHO) (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available from: http://www.who.int/medicines/publications/WHO-PPL-ShortSummary_25Feb-ET_NM_WHO.pdf. Accessed 12 Dec 2020

  7. European Centre for Disease Prevention and Control (2019) Surveillance of antimicrobial resistance in Europe-annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2019. https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2019.pdf. Accessed 20 Jan 2021

  8. van Duin D, Arias CA, Komarow L, Chen L, Hanson BM, Weston G, et al. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study. Lancet Infect Dis. 2020;20:731–41.

    Article  Google Scholar 

  9. Kazmierczak KM, Karlowsky JA, de Jonge BLM, Stone GG, Sahm DF. Epidemiology of carbapenem resistance determinants identified in meropenem-nonsusceptible Enterobacterales collected as part of a global surveillance program, 2012 to 2017. Antimicrob Agents Chemother. 2021;65:e0200020.

    Article  Google Scholar 

  10. Spaziante M, Oliva A, Ceccarelli G, Venditti M. What are the treatment options for resistant Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria? Expert Opin Pharmacother. 2020;21:1781–7.

    Article  Google Scholar 

  11. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58:2322–8.

    Article  Google Scholar 

  12. Tsakris A, Poulou A, Pournaras S, Voulgari E, Vrioni G, Themeli-Digalaki K, et al. A simple phenotypic method for the differentiation of metallo-beta-lactamases and class A KPC carbapenemases in Enterobacteriaceae clinical isolates. J Antimicrob Chemother. 2010;65:1664–71.

    Article  CAS  Google Scholar 

  13. Poulou A, Grivakou E, Vrioni G, Koumaki V, Pittaras T, Pournaras S, et al. Modified CLSI extended-spectrum β-lactamase (ESBL) confirmatory test for phenotypic detection of ESBLs among Enterobacteriaceae producing various β-lactamases. J Clin Microbiol. 2014;52:1483–9.

    Article  Google Scholar 

  14. Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis. 2011;70:119–23.

    Article  CAS  Google Scholar 

  15. Diancourt L, Passet V, Verhoef J, Grimont PA, Brisse S. Multilocus sequence typing of Klebsiella pneumoniae nosocomial isolates. J Clin Microbiol. 2005;43:4178–82.

    Article  CAS  Google Scholar 

  16. European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation for MICs and zone diameters: version 10.0, valid from 2020–01–01. EUCAST, Basel, Switzerland; 2020.

  17. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; 30th ed. (M100-S30); 2020.

  18. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268–81.

    Article  CAS  Google Scholar 

  19. Giakkoupi P, Xanthaki A, Kanelopoulou M, Vlahaki A, Miriagou V, Kontou S, et al. VIM-1 Metallo-beta-lactamase-producing Klebsiella pneumoniae strains in Greek hospitals. J Clin Microbiol. 2003;41:3893–6.

    Article  CAS  Google Scholar 

  20. Maltezou HC, Giakkoupi P, Maragos A, Bolikas M, Raftopoulos V, Papahatzaki H, et al. Outbreak of infections due to KPC-2-producing Klebsiella pneumoniae in a hospital in Crete (Greece). J Infect. 2009;58:213–9.

    Article  CAS  Google Scholar 

  21. Galani I, Karaiskos I, Karantani I, Papoutsaki V, Maraki S, Papaioannou V, et al. Epidemiology and resistance phenotypes of carbapenemase-producing Klebsiella pneumoniae in Greece, 2014 to 2016. Euro Surveill. 2018. https://doi.org/10.2807/1560-7917.ES.2018.23.30.1700775.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Karampatakis T, Antachopoulos C, Iosifidis E, Tsakris A, Roilides E. Molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae in Greece. Future Microbiol. 2016;11:809–23.

    Article  CAS  Google Scholar 

  23. Piazza A, Comandatore F, Romeri F, Brilli M, Dichirico B, Ridolfo A, et al. Identification of blaVIM-1 gene in ST307 and ST661 Klebsiella pneumoniae clones in Italy: old acquaintances for new combinations. Microb Drug Resist. 2019;25:787–90.

    Article  CAS  Google Scholar 

  24. Giakkoupi P, Papagiannitsis CC, Miriagou V, Pappa O, Polemis M, Tryfinopoulou K, et al. An update of the evolving epidemic of blaKPC-2-carrying Klebsiella pneumoniae in Greece (2009–10). J Antimicrob Chemother. 2011;66:1510–3.

    Article  CAS  Google Scholar 

  25. Papagiannitsis CC, Giakkoupi P, Kotsakis SD, Tzelepi E, Tzouvelekis LS, Vatopoulos AC, et al. OmpK35 and OmpK36 porin variants associated with specific sequence types of Klebsiella pneumoniae. J Chemother. 2013;25:250–4.

    Article  CAS  Google Scholar 

  26. Avgoulea K, Di Pilato V, Zarkotou O, Sennati S, Politi L, Cannatelli A, et al. Characterization of extensively drug-resistant or pandrug-resistant Sequence Type 147 and 101 OXA-48-producing Klebsiella pneumoniae causing bloodstream infections in patients in an intensive care unit. Antimicrob Agents Chemother. 2018;62:e02457-e2517.

    Article  CAS  Google Scholar 

  27. de Jonge BL, Karlowsky JA, Kazmierczak KM, Biedenbach DJ, Sahm DF, Nichols WW. In vitro susceptibility to ceftazidime–avibactam of carbapenem-nonsusceptible Enterobacteriaceae isolates collected during the INFORM global surveillance study (2012 to 2014). Antimicrob Agents Chemother. 2016;60:3163–9.

    Article  Google Scholar 

  28. Rossolini GM, Stone GG. Assessment of the in vitro activity of ceftazidime/avibactam against a global collection of multidrug-resistant Klebsiella spp. from the INFORM surveillance programme (2015–2017). Int J Antimicrob Agents. 2020;56:106111.

    Article  CAS  Google Scholar 

  29. Spiliopoulou I, Kazmierczak K, Stone GG. In vitro activity of ceftazidime/avibactam against isolates of carbapenem-non-susceptible Enterobacteriaceae collected during the INFORM global surveillance programme (2015–17). J Antimicrob Chemother. 2020;75:384–91.

    Article  CAS  Google Scholar 

  30. Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61:e00567-e617.

    Article  CAS  Google Scholar 

  31. Hackel MA, Lomovskaya O, Dudley MN, Karlowsky JA, Sahm DF. In vitro activity of meropenem–vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae. Antimicrob Agents Chemother. 2017;62:e01904-e1917.

    PubMed  PubMed Central  Google Scholar 

  32. Pfaller MA, Huband MD, Mendes RE, Flamm RK, Castanheira M. In vitro activity of meropenem/vaborbactam and characterisation of carbapenem resistance mechanisms among carbapenem-resistant Enterobacteriaceae from the 2015 meropenem/ vaborbactam surveillance programme. Int J Antimicrob Agents. 2018;52:144–50.

    Article  CAS  Google Scholar 

  33. Galani I, Souli M, Nafplioti K, Adamou P, Karaiskos I, Giamarellou H, et al. In vitro activity of imipenem–relebactam against non-MBL carbapenemase-producing Klebsiella pneumoniae isolated in Greek hospitals in 2015–2016. Eur J Clin Microbiol Infect Dis. 2019;38:1143–50.

    Article  CAS  Google Scholar 

  34. Yang Q, Zhang H, Yu Y, Kong H, Duan Q, Wang Y, et al. In vitro activity of imipenem/relebactam against Enterobacteriaceae isolates obtained from intra-abdominal, respiratory tract, and urinary tract infections in China: Study for Monitoring Antimicrobial Resistance Trends (SMART), 2015–2018. Clin Infect Dis. 2020;71:S427–35.

    Article  CAS  Google Scholar 

  35. Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. In vitro activity of imipenem/relebactam against Gram-negative bacilli from pediatric patients-Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program 2015–2017. J Pediatric Infect Dis Soc. 2021;10:274–81.

    Article  CAS  Google Scholar 

  36. Lob SH, Hackel MA, Young K, Motyl MR, Sahm DF. Activity of imipenem/ relebactam and comparators against gram-negative pathogens from patients with bloodstream infections in the United States and Canada—SMART 2018–2019. Diagn Microbiol Infect Dis. 2021;100:115421.

    Article  CAS  Google Scholar 

  37. Zhang Y, Lin X, Bush K. In vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline. J Antibiot. 2016;69:600–4.

    Article  CAS  Google Scholar 

  38. Livermore DM, Mushtaq S, Warner M, Woodford N. In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60:3840–4.

    Article  CAS  Google Scholar 

  39. Galani I, Nafplioti K, Adamou P, Karaiskos I, Giamarellou H, Souli M, et al. Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance. BMC Infect Dis. 2019;19:167.

    Article  Google Scholar 

  40. Martins AF, Bail L, Ito CAS, da Silva NK, Dalmolin TV, Martins AS, et al. Antimicrobial activity of plazomicin against Enterobacteriaceae-producing carbapenemases from 50 Brazilian medical centers. Diagn Microbiol Infect Dis. 2018;90:228–32.

    Article  CAS  Google Scholar 

  41. Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother. 2011;66:48–53.

    Article  CAS  Google Scholar 

  42. Castanheira M, Sader HS, Mendes RE, Jones RN. Activity of plazomicin tested against Enterobacterales isolates collected from U.S. Hospitals in 2016–2017: effect of different breakpoint criteria on susceptibility rates among aminoglycosides. Antimicrob Agents Chemother. 2020;64:e02418–9.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Microbiology and Microbial Pathogenesis, University Hospital of Heraklion, Heraklion, Crete, Greece

    Sofia Maraki, Panagiotis Moraitis, Dimitra Stafylaki & Anna Kasimati

  2. University of Crete Medical School, Heraklion, Crete, Greece

    Viktoria Eirini Mavromanolaki

  3. Laboratory of Clinical Microbiology and Molecular Microbiology, School of Medicine, University of Crete, Heraklion, Crete, Greece

    Eleni Magkafouraki & Effie Scoulica

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Contributions

SM, VEM, DS, and AK conceived and designed the study. SM, VEM, AK, PM, ES, and EM carried out the microbiologic and genotypic analyses. Data analysis and interpretation were performed by SM, DS, A K, PM, ES, and EM. The first draft of the manuscript was written by SM, VEM, and ES, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sofia Maraki.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was approved by the Ethical Committee of the University Hospital of Heraklion and met the guidelines of Helsinki declarations.

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The original online version of this article was revised: In the “Abstract” and in the “Materials and Methods” section: “were evaluated by Etest.” was corrected to “were evaluated by the MIC Test Strip method.”

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Maraki, S., Mavromanolaki, V.E., Magkafouraki, E. et al. Epidemiology and in vitro activity of ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam, eravacycline, plazomicin, and comparators against Greek carbapenemase-producing Klebsiella pneumoniae isolates. Infection 50, 467–474 (2022). https://doi.org/10.1007/s15010-021-01735-1

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