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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. ISSN 1098-6596

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 carbapenem-resistant Enterobacteriaceae (CRE) strains tested. Overall, LYS228 demonstrated potent activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates. Based upon MIC90 values, LYS228 (MIC90= 1 μg/mL) was ≥32-fold more active against these strains than were aztreonam, ceftazidime, ceftazidime/avibactam, cefepime, and meropenem. The MIC90 value for tigecyline 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 MBC to MIC ratios (≤4) against 97.4% (264/271) of the Enterobacteriaceae strains tested. In time-kill studies, LYS228 consistently achieved 3-log10 reduction in colony-forming units (CFU)/mL (≥99.9% killing) at concentrations ≥4X the MIC for E. 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
Date Deposited: 01 Sep 2018 00:45
Last Modified: 01 Sep 2018 00:45
URI: https://oak.novartis.com/id/eprint/36715

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