Carbapenem-Resistant Klebsiellae Susceptible to Ceftibuten and VNRX-5236

Designated an “urgent threat” by the Centers for Disease Control and Prevention (CDC), Klebsiellae pneumoniae has developed carbapenem resistance through mutational and acquired mechanisms. In a study presented virtually at IDWeek 2021, investigators tested the susceptibility of Klebsiellae to ceftibuten and VNRX-5236.

VNRX-5236 is a bicyclic boronate β-lactamase inhibitor (BLI) that combines oral bioavailability (via etzadroxil prodrug VNRX-7145) with activity against all 3 Ambler classes of serine β-lactamases.

Investigators tested the activity of ceftibuten (CTB)/VNRX-5236 against 200- carbapenem-resistant Klebsiellae. Of these, 193 contained class A KPC enzymes, one expressed a class B NDM enzyme, and six had a class D OXA-48 enzyme (or a variant). Investigators determined the minimum inhibitory concentrations (MIC) using broth microdilution ThermoFisher Sensititre system with custom assay panels. MICs were interpreted using CLSI M100 Ed. 30, with the exception of the EUCAST breakpoint for CTB (S≤1 µg/mL), which was used for CTB and applied for comparative purposes to CTB/VNRX-5236 MICs where VNRX-5236 was fixed at 4 µg/mL. The investigators utilized American Type Culture Collection strains to ensure quality control.

The results showed 92.5% of strains studied in the collection to be at least provisionally susceptible to CTB/VNRX-5236. In comparison, strains were 95.5% susceptible to meropenem-vaborbactam (MVB), and 98% susceptible to ceftazidime-avibactam (CZA).

MIC50s were in the susceptible range for CZA, MVB, and CTB/VNRX-5236; MIC50s were resistant for CTB, ceftazidime (CAZ) and meropenem (MEM). MIC90s were in the susceptible range for CZA, MVB, and CTB/VNRX-5236, and the resistant range for CAZ, MEM, and CTB. In total, 1 of 4 CZA-resistant and 3 of 9 MVB non-susceptible strains were provisionally susceptible to CTB/VNRX-5236.

The study found that adding VNRX-5236 to CTB enhanced the activity against Klebsiella isolates tested. Combined, they reached a total of 92.5% susceptibility. The investigators noted that VNRX-5236 has a broader spectrum of activity than preexisting oral BLIs, making it a potential new treatment option for resistant infections.