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In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae.
Int J Antimicrob Agents. 2020 Jul; 56(1):105925.IJ

Abstract

OBJECTIVES

To evaluate the potential clinical in vitro efficacy of novel β-lactam/β-lactamase-inhibitor combinations - including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) - against contemporary multidrug-resistant (MDR) Enterobacteriaceae.

METHODS

Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative β-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant β-lactamases covering representatives from all four Ambler classes of β-lactamases, were tested using a fluorescence-based assay.

RESULTS

Using recombinant proteins, all four inhibitors were highly active against the tested class A serine β-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-β-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A β-lactamases (ESBLs) than the established inhibitors.

CONCLUSION

The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of β-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies.

Authors+Show Affiliations

Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom.Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; Charles River Laboratories, Chesterford Research Park, Saffron Walden, United Kingdom.Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom.Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom.Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom.Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom.Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom. Electronic address: jurgen.brem@chem.ox.ac.uk.Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff, United Kingdom; School of Cellular & Molecular Medicine, Biomedical Sciences Building, University Walk, Bristol, United Kingdom. Electronic address: jonathan.tyrrell@bristol.ac.uk.

Pub Type(s)

Evaluation Study
Journal Article

Language

eng

PubMed ID

32084512

Citation

Tselepis, Lucas, et al. "In Vitro Efficacy of Imipenem-relebactam and cefepime-AAI101 Against a Global Collection of ESBL-positive and Carbapenemase-producing Enterobacteriaceae." International Journal of Antimicrobial Agents, vol. 56, no. 1, 2020, p. 105925.
Tselepis L, Langley GW, Aboklaish AF, et al. In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae. Int J Antimicrob Agents. 2020;56(1):105925.
Tselepis, L., Langley, G. W., Aboklaish, A. F., Widlake, E., Jackson, D. E., Walsh, T. R., Schofield, C. J., Brem, J., & Tyrrell, J. M. (2020). In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae. International Journal of Antimicrobial Agents, 56(1), 105925. https://doi.org/10.1016/j.ijantimicag.2020.105925
Tselepis L, et al. In Vitro Efficacy of Imipenem-relebactam and cefepime-AAI101 Against a Global Collection of ESBL-positive and Carbapenemase-producing Enterobacteriaceae. Int J Antimicrob Agents. 2020;56(1):105925. PubMed PMID: 32084512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae. AU - Tselepis,Lucas, AU - Langley,Gareth W, AU - Aboklaish,Ali F, AU - Widlake,Emma, AU - Jackson,Dana E, AU - Walsh,Timothy R, AU - Schofield,Chris J, AU - Brem,Jürgen, AU - Tyrrell,Jonathan M, Y1 - 2020/02/18/ PY - 2019/06/13/received PY - 2020/01/03/revised PY - 2020/02/11/accepted PY - 2020/2/23/pubmed PY - 2021/4/20/medline PY - 2020/2/22/entrez KW - AAI101 (enmetazobactam) KW - Avibactam KW - Carbapenemase KW - Extended spectrum β-lactamase KW - Relebactam KW - β-lactamase inhibitor SP - 105925 EP - 105925 JF - International journal of antimicrobial agents JO - Int J Antimicrob Agents VL - 56 IS - 1 N2 - OBJECTIVES: To evaluate the potential clinical in vitro efficacy of novel β-lactam/β-lactamase-inhibitor combinations - including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) - against contemporary multidrug-resistant (MDR) Enterobacteriaceae. METHODS: Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative β-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant β-lactamases covering representatives from all four Ambler classes of β-lactamases, were tested using a fluorescence-based assay. RESULTS: Using recombinant proteins, all four inhibitors were highly active against the tested class A serine β-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-β-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A β-lactamases (ESBLs) than the established inhibitors. CONCLUSION: The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of β-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/32084512/In_vitro_efficacy_of_imipenem_relebactam_and_cefepime_AAI101_against_a_global_collection_of_ESBL_positive_and_carbapenemase_producing_Enterobacteriaceae_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(20)30068-6 DB - PRIME DP - Unbound Medicine ER -