Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain

Juan Carlos Vázquez-Ucha; Isaac Alonso-Garcia; Paula Guijarro-Sánchez; Cristina Lasarte-Monterrubio; Laura Álvarez-Fraga; Arnau Cendón-Esteve; Michelle Outeda; Romina Maceiras; Andrea Peña-Escolano; Marta Martínez-Guitián; Jorge Arca-Suárez; Germán Bou; Alejandro Beceiro; GEMARA-SEIMC/REIPI Enterobacterales Study Group

doi:10.1016/j.ijantimicag.2023.106738

Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain

Int J Antimicrob Agents. 2023 Apr;61(4):106738. doi: 10.1016/j.ijantimicag.2023.106738. Epub 2023 Feb 3.

Authors

Affiliations

¹ Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, A Coruña, Spain; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: Juan.Carlos.Vazquez.Ucha@sergas.es.
² Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, A Coruña, Spain.
³ NANOBIOFAR, Centre for Research in Molecular Medicine and Chronic Diseases, Universidad de Santiago de Compostela, Santiago de Compostela, Spain; Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, University of A Coruña, A Coruña, Spain.
⁴ Microbiology Department, University Hospital A Coruña, Institute of Biomedical Research of A Coruña, A Coruña, Spain; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.

PMID: 36736925
DOI: 10.1016/j.ijantimicag.2023.106738

Abstract

Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel β-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. β-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum β-lactamases and class C β-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.

Keywords: Aztreonam; CPE; Enterobacterales; Metallo-β-lactamase; WGS; β-lactamase inhibitors.

Publication types

Multicenter Study

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Azabicyclo Compounds / pharmacology
Aztreonam* / pharmacology
Drug Combinations
Microbial Sensitivity Tests
Spain
beta-Lactamase Inhibitors* / pharmacology
beta-Lactamase Inhibitors* / therapeutic use
beta-Lactamases / genetics

Substances

zidebactam
Aztreonam
beta-Lactamase Inhibitors
Anti-Bacterial Agents
avibactam
taniborbactam
beta-Lactamases
Azabicyclo Compounds
Drug Combinations