Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-beta-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection

Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate beta-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine beta-lactamases (Ambler class A, C, and D). In vivo, ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales, including MDR organisms, extended-spectrump-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 Ag/mL. beta-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected beta-lactam-resistant isolate subsets. At <= 1 mu g/mL, ceftibuten-ledaborbactam (MIC90, 0.25 mu g/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacinnonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibutenresistant (MIC >1 mu g/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-beta-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (Mic a , 025 mu g/mL), 91.5% of CTX-M-1 group (MIC90, 0.5 mu g/mL), and 88.2% of SHV-positive (MIC90, 2 mu g/mL) isolates at <= 1 mu g/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90, 2 mu g/mL) and 82.9% of OXA-48-group-positive (MIC90, 2 mu g/mL) isolates at <= 1 mu g/mL. Continued development of ceftibuten-ledaborbactam appears warranted.