In vitro activity of the orally bioavailable ceftibuten/VNRX-7145 (VNRX-5236 etzadroxil) combination against a challenge set of Enterobacterales pathogens carrying molecularly characterized β-lactamase genes

OBJECTIVES: This study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the β-lactamase inhibitor VNRX-7145 and comparators against a challenge set of Gram-negative pathogens. METHODS: Two hundred and five Enterobacterales carrying plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like with KPC (3) encoding genes were selected. Susceptibility was determined by broth microdilution. VNRX-5236 and avibactam were tested at a fixed concentration of 4 mg/L. RESULTS: Ceftibuten/VNRX-5236 (MIC(50/90) 0.12/1 mg/L) MIC values were 256-fold lower than those of ceftibuten (MIC(50/90) 32/256 mg/L) for all Enterobacterales and 2- to 4-fold lower than those of ceftazidime/avibactam (MIC(50/90) 0.5/2 mg/L). For isolates producing a plasmid-encoded AmpC, VNRX-5236 decreased ceftibuten MIC (MIC(50/90) 0.12/1 mg/L) by at least 512-fold compared with ceftibuten (MIC(50/90) 128/>256 mg/L). Ceftibuten/VNRX-5236 (MIC(50/90) 0.06/0.12 mg/L) and meropenem (MIC(50/90) ≤0.03/0.06 mg/L; 100% susceptible) showed comparable activities against ESBL isolates and these agents had MIC(90) values 4- to 8-fold lower than that of ceftazidime/avibactam (MIC(50/90) 0.25/0.5 mg/L; 100% susceptible). Ceftibuten/VNRX-5236 (MIC(50/90) 0.12/0.5 mg/L) had the lowest MIC for KPC producers, followed by ceftazidime/avibactam (MIC(50/90) 2/4 mg/L; 98.0% susceptible). The same MIC(90) values were obtained for ceftibuten/VNRX-5236 (MIC(50/90) 0.25/1 mg/L) and ceftazidime/avibactam (MIC(50/90) 1/1 mg/L; 100.0% susceptible) for isolates carrying bla(OXA-48-like). VNRX-5236 decreased the ceftibuten MIC at least 16-fold for three isolates carrying bla(OXA-48-like) and bla(KPC). CONCLUSIONS: VNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common serine β-lactamases, including ESBL, AmpC and the KPC and OXA-48-like carbapenemases. Ceftibuten/VNRX-5236 may have potential as an oral treatment for infections caused by resistant Enterobacterales, while sparing carbapenems.