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In vitro activity of imipenem-relebactam against non-MBL carbapenemase-producing Klebsiella pneumoniae isolated in Greek hospitals in 2015–2016

  • Irene GalaniEmail author
  • Maria Souli
  • Konstantina Nafplioti
  • Panagiora Adamou
  • Ilias Karaiskos
  • Helen Giamarellou
  • Anastasia Antoniadou
  • On Behalf Of The Study Collaborators
Original Article

Abstract

Relebactam is a β-lactamase inhibitor of class A and class C β-lactamases, including carbapenemases. We evaluated the ability of relebactam to restore imipenem susceptibility against a collection of Klebsiella pneumoniae isolates from Greek hospitals. We tested 314 non-MBL carbapenemase-producing K. pneumoniae consecutive clinical strains isolated from unique patients at 18 hospitals in Greece, between November 2014 and December 2016. Susceptibility testing of imipenem, imipenem-relebactam, meropenem, doripenem, gentamicin, and colistin was performed using broth microdilution. Additionally, MICs of ceftazidime-avibactam, fosfomycin, and tigecycline were determined by MIC Test Strips. MICs were interpreted per EUCAST breakpoints. Imipenem-relebactam MICs were interpreted using the breakpoints proposed for imipenem. Carbapenemase genes were detected using PCR. Whole genome sequencing was performed for selected isolates. Imipenem-relebactam inhibited 98.0% of the KPC-producing isolates at ≤ 2 mg/L (MIC50/90, 0.25/1 mg/L) and was considerably more active than imipenem (MIC50/90, 32/> 64 mg/L). Reduced activity of imipenem-relebactam was rarely detected (2%) and was associated with chromosomal factors (ompK35 disruption and/or mutated ompK36). Only ceftazidime-avibactam showed in vitro activity comparable to imipenem-relebactam (99.6% susceptible). Relebactam provided only weak potentiation of imipenem activity against K. pneumoniae with class D OXA-48-like enzymes. Relebactam exhibited strong potential for restoring the in vitro activity of imipenem against KPC-producing K. pneumoniae, lowering the imipenem MIC50 and MIC90 from 32 to 0.25 mg/L, and from > 64 to 1 mg/L, respectively. Production of KPC carbapenemase represents the main cause of carbapenem resistance among K. pneumoniae in Greek hospitals (66.5%), and this carbapenemase appears to be very well inhibited by relebactam.

Keywords

Relebactam Carbapenemase KPC OXA-48 K. pneumoniae 

Notes

Acknowledgments

The authors would like to acknowledge the staff from the Microbiology Departments of the 18 participating hospitals, for providing the test isolates. Some of these data were presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases, 2018, Madrid, Spain (abstract P1048).

Study collaborators

Sofia Maraki, Viktoria Eirini Mavromanolaki, University Hospital of Heraklion, Heraklion; Vassiliki Papaioannou, Sofia Tsiplakou, ‘KAT’ Hospital, Athens; Polizo Kazila, Ioanna Diamanti, Cancer Hospital of Thessaloniki ‘THEAGENEIO’, Thessaloniki; Helen Tsorlini, Helen Katsifa, “G. Papanikolaou” General Hospital of Thessaloniki, Thessaloniki; Nikoletta Charalampaki, Panagiota Giannopoulou, Eleftheria Trikka-Graphakos, “THRIASSIO” General Hospital, Elefsina, Athens; Marina Toutouza, Hippokration Athens General Hospital, Athens; Helen Vagiakou, General Hospital of Athens “G.Gennimatas“, Athens; Konstantinos Pappas, Athens Naval Hospital, Athens; Anna Kyratsa, Angeliki Paschali, General Hospital of Corfu, Corfu; Konstantina Kontopoulou, General Hospital of Thessaloniki “G. Gennimatas“, Thessaloniki; Olga Legga, General Hospital of Lamia, Lamia; Efthymia Petinaki, University Hospital of Larissa, Larissa; Helen Papadogeorgaki, Vassiliki Papoutsaki, Hygeia General Hospital, Athens; Efrosini Chinou, St Savvas, Cancer Hospital, Athens; Eleni Moraitou, Evangellos Vogiatzakis, “Sotiria” General and Chest Diseases Hospital, Athens; Paraskevi Chra, Vassiliki Baka, Korgialenio Benakio Hellenic Red Cross Hospital, Athens; Maria Damala, Eleni Prifti, “Alexandra” General Hospital of Athens, Athens

Funding

Funding for this research was provided by MSD - Merck Sharp & Dohme, Hellas.

Compliance with ethical standards

Conflict of interest

IG has received research grand and speaker honorarium from ACHAOGEN and speaker honorarium and financial support for attending symposia from MSD; MS has received research grand from ACHAOGEN; HG has received research grand from Pfizer; AA has received research grand by MSD. All other authors: none to declare.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Disclaimer

The funding company did not participate in the study design, data collection, analysis, or, interpretation of data preparation of the manuscript, and the decision to submit the manuscript for publication.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Irene Galani
    • 1
    • 2
    Email author
  • Maria Souli
    • 1
  • Konstantina Nafplioti
    • 1
  • Panagiora Adamou
    • 1
  • Ilias Karaiskos
    • 3
  • Helen Giamarellou
    • 3
  • Anastasia Antoniadou
    • 1
  • On Behalf Of The Study Collaborators
  1. 1.4th Department of Internal Medicine, Infectious Diseases Laboratory, Molecular Biology Section, School of MedicineNational and Kapodistrian University of AthensAthensGreece
  2. 2.University General Hospital “ATTIKON”ChaidariGreece
  3. 3.1st Internal Medicine & Infectious Diseases ClinicHygeia General HospitalMarousiGreece

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