Blais, Johanne, Lopez, Sara, Li, Cindy, Ruzin, Alexey, Ranjikar, Srijan, Dean, Charles, Leeds, Jennifer, Casarez, Anthony, 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