Activity of β-lactam/taniborbactam (VNRX-5133) combinations against carbapenem-resistant Gram-negative bacteria

Mushtaq, Shazad, Vickers, Anna, Doumith, Michel, Ellington, Matthew J., Woodford, Neil and Livermore, David (2020) Activity of β-lactam/taniborbactam (VNRX-5133) combinations against carbapenem-resistant Gram-negative bacteria. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453 (In Press)

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Background : Boronates are of growing interest as β-lactamase inhibitors. The only marketed analogue, vaborbactam, targets KPC carbapenemases, but taniborbactam (VNRX-5133, Venatorx) has a broader spectrum. Materials and methods : MICs of cefepime and meropenem were determined combined with taniborbactam or avibactam for carbapenem-resistant UK isolates. β-Lactamase genes and porin alterations were sought by PCR or sequencing. Results : Taniborbactam potentiated partner β-lactams against (i) Enterobacterales with KPC, other Class A, OXA-48-like, VIM and NDM (not IMP) carbapenemases and against (ii) Enterobacterales inferred to have combinations of ESBL or AmpC activity and impermeability. Potentiation of cefepime (the partner for clinical development) by taniborbactam was slightly weaker than by avibactam for Enterobacterales with KPC or OXA-48-like carbapenemases, but MICs of cefepime/taniborbactam were similar to those of ceftazidime/avibactam and the spectrum was wider. MICs of cefepime/taniborbactam nonetheless remained >8+4 mg/L for 22-32% of NDM-producing Enterobacterales. Correlates of raised cefepime/taniborbactam MICs among these NDM Enterobacterales were: a cefepime MIC >128 mg/L, particular sequence types, also, for Escherichia coli only: (i) the blaNDM variant (even though published data suggest all are inhibited similarly), (ii) inserts in PBP3, and (iii) raised aztreonam/avibactam MICs. Little or no potentiation of cefepime or meropenem was seen for Pseudomonas aeruginosa and Acinetobacter baumannii with MBLs, probably reflecting less uptake or more efflux. Potentiation of cefepime was seen for Stenotrophomonas maltophilia and Elizabethkingia meningoseptica, which have both chromosomal ESBLs and MBLs. Conclusion : Taniborbactam broadly reversed cefepime or meropenem non-susceptibility in Enterobacterales, less reliably for non-fermenters.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 21 Aug 2020 00:04
Last Modified: 21 Aug 2020 00:04

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