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In vitro activity of LYS228, a novel monobactam antibiotic, against multidrug-resistant enterobacteriaceae

Blais, Johanne and Lopez, Sara and Li, Cindy and Ruzin, Alexey and Ranjikar, Srijan and Dean, Charles and Leeds, Jennifer and Casarez, Anthony and Simmons, Bob and Reck, Folkert (2018) In vitro activity of LYS228, a novel monobactam antibiotic, against multidrug-resistant enterobacteriaceae. Antimicrobial Agents and Chemotherapy, 62 (10). pp. 1-10. ISSN 10986596

Abstract

LYS228 is a novel monobactam with potent activity against Enterobacteriaceae. LYS228 is stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency against the majority of extended-spectrum β-lactamase (ESBL)-producing and carbapenemresistant Enterobacteriaceae strains tested. Overall, LYS228 demonstrated potent activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates. Based on MIC90 values, LYS228 (MIC90, 1 μg/ml) was ≥32-fold more active against those strains than were aztreonam, ceftazidime, ceftazidime-avibactam, cefepime, and meropenem. The tigecycline MIC90 was 4 μg/ml against the strains tested. Against Enterobacteriaceae isolates expressing ESBLs (n = 37) or displaying carbapenem resistance (n = 77), LYS228 had MIC90 values of 1 and 4 μg/ml, respectively. LYS228 exhibited potent bactericidal activity, as indicated by low minimal bactericidal concentration (MBC) to MIC ratios (MBC/MIC ratios of ≤4) against 97.4% of the Enterobacteriaceae strains tested (264/271 strains). In time-kill studies, LYS228 consistently achieved reductions in CFU per milliliter of 3 log10 units (≥99.9% killing) at concentrations ≥4× MIC for Escherichia coli and K. pneumoniae reference strains, as well as isolates encoding TEM-1, SHV-1, CTX-M-14, CTX-M-15, KPC-2, KPC-3, and NDM-1 β-lactamases.

Item Type: Article
Keywords: Enterobacteriaceae LYS228 Monobactams
Date Deposited: 01 Nov 2018 00:45
Last Modified: 01 Nov 2018 00:45
URI: https://oak.novartis.com/id/eprint/35532

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