687. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Acinetobacter spp.

Abstract

Background Acinetobacter spp. resistant to common antibiotics have become a worrying cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (figure) which facilitates transport to the periplasm are being developed which show promise against Gram-negative organisms including Acinetobacter spp.MethodsYU253911, an example of this new class of antibacterials, was characterized in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a collection of 200 previously described (whole-genome sequencing) Acinetobacter isolates including 98 carbapenem-resistant A. baumannii strains. YU253911’s antimicrobial activity was also evaluated in combination with complementary PBP agents and β-lactamase inhibitors by MIC and disc diffusion testing. All studies were performed according to current Clinical and Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Breakpoints for ceftazidime were arbitrarily chosen as reference.ResultsUsing ceftazidime (breakpoint ≤8 μg/mL) as a comparator, 175 of the 200 Acinetobacter isolates were susceptible to YU253911, which possessed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL. This compared favorably to all previously tested β-lactams including penicillins, cephalosporins, monobactams and carbapenems (MIC50s 2 to >16 μg/mL). Against the subset of carbapenem-resistant A. baumannii isolates, YU253911’s potency was similar with an MIC50 of 1 μg/mL. Genetic analysis showed β-lactamase genes, including OXA-23 and other carbapenemases, were common in both YU253911-resistant and susceptible strains.ConclusionYU253911 demonstrates promising in vitro potency against a collection of Acinetobacter isolates and compares favorably to β-lactam antibiotics. Understanding interactions with PBP agents and β lactamase inhibitors is being explored as well as further studies on the mechanism of resistance. Disclosures All authors: No reported disclosures.