1737. Xeruborbactam (QPX) Potentiates the Activity of β-Lactam (BL) Antibiotics Against a Diverse Group of Highly Drug-Resistant Enterobacterales (ENT)

Abstract

Abstract Background Antibiotic resistant ENT are a growing threat worldwide. QPX is an ultra-broad-spectrum β-lactamase inhibitor (BLI) with potent inhibition of classes A and D, and many metallo-β-lactamases, which has potential to fill the void of currently available BL-BLIs. Methods We evaluated QPX (fixed concentration of 8 µg/mL) in combination with meropenem (MEM), cefepime (FEP) and aztreonam (ATM) against a diverse group of ENT clinical isolates selected from a worldwide repository. Antibiotic resistance determinants were assessed by mining whole-genome sequencing data generated using Illumina MiSeq. Results Klebsiella spp, Enterobacter spp, and Escherichia coli were most common among the 90 isolates tested (Fig. 1). 71% (64) produced carbapenemases (Fig. 2): 3 isolates produced both class A and B carbapenemases. 11% of isolates harbored mutations in ompK 36/ompC genes. 57% (51) were resistant to MEM, 31% to imipenem-relebactam, 17% (15) to ceftazidime-avibactam (CZA), and 9% to MEM-vaborbactam (MVB). ENT-resistant to CZA were due to production of class B, D or KPC-3 variants, or ompC mutation in a K. aerogenes isolate. ENT-resistant to MVB were due to class B or D enzymes, or class A with ompK36 or ompC mutations. MIC distributions of BL with or without QPX against all isolates tested are presented in Fig. 3. Addition of QPX to MEM, FEP and AMT reduced MIC50s and MIC90s of these agents (Fig. 3; p< 0.0001). Of note, addition of QPX reduced MEM MICs more than did vaborbactam (median 533- versus 24-fold; p=0.0006). QPX reduced MICs of MEM, FEP and ATM to levels below respective breakpoints for non-susceptibility (Fig. 3). MIC distribution of ENT isolates stratified by the types of carbapenemases are presented in Fig. 4. QPX potentiated activity of MEM, FEP or ATM against ENT, regardless of whether they produced class A, B or D carbapenemases. Conclusion QPX enhanced activity of MEM, FEP and ATM against carbapenemase-producing or other carbapenem-resistant ENT (CRE), regardless of species or other resistance determinants. Most remarkably, QPX rendered each BL equally active against CRE. The expanded spectrum of QPX against class B and D carbapenemases addresses a major unmet need against CRE. Disclosures Cornelius J. Clancy, MD, receives research funding paid to his institution from Astellas and Merck: Grant/Research Support|serves as an advisory Board member for Astellas, Cidara, and Scynexis, served on the advisory board for Merck, Qpex Biopharma, and Shionogi: Advisor/Consultant|Venatorx and Needham & Associates: Advisor/Consultant.