P1181 Selection of ceftibuten as the partner antibiotic for the oral beta-lactamase inhibitor VNRX-7145 Jodie Hamrick*1, Cassandra Chatwin1, Kaitlyn John1, Christopher Burns1, Luigi Xerri1, Greg Moeck1, Daniel C. Pevear1

1 VenatoRx Pharmaceuticals Inc., Malvern, United States Background: VNRX-7145 is a novel cyclic boronate β-lactamase inhibitor with oral bioavailability in several pre- clinical species. In vivo, VNRX-7145 undergoes biotransformation to the active VNRX-5236 with potent inhibitory activity against Ambler class A, C, and D enzymes, including those that hydrolyze carbapenems. When combined with oral β-lactams, VNRX-5236 is able to restore their antibacterial activity against MDR strains of Enterobacteriaceae. Eight commercially available oral antibiotics (ceftibuten, cefuroxime, cefixime, cefditoren, cefpodoxime cephalexin, cefdinir, and amoxicillin were investigated in combination with VNRX-5236 to select the one with the best overall antibacterial profile. Materials/methods: Broth microdilution minimum inhibitory concentration (MIC) assays were conducted according to CLSI guidelines. Antibacterials were titrated while VNRX-5236 was fixed at a concentration of 4 mg/L. Activity of the VNRX-5236 combinations was compared to antibacterial agents alone, amoxicillin/clavulanic acid and levofloxacin in 100 isolates of Enterobacteriaceae expressing Class A ESBL (25), Class A KPC (N=25), Class C (N=25), and Class D OXA-48 (N=25) enzymes. β-lactamase genes were verified using polymerase chain reaction (PCR) while expression of these genes was determined phenotypically. Results: In the four enzyme subsets tested (ESBL, KPC, Class C, and OXA-48-like) VNRX-5236 added to ceftibuten was the most potent antibacterial combination, with an MIC90 of ≤ 1 mg/L across enzyme subgroups. The second best performing partner antibacterial was cefixime. The rescue of cefixime was similar to ceftibuten in ESBL- expressing strains of Enterobacteriaceae, but was slightly weaker against strains expressing AmpC, KPC and OXA- 48. Amoxicillin was the weakest partner being rescued in the lowest percentage of strains in each subset. Conclusions: VNRX-5236 in combination with ceftibuten was the most potent combination across clinical isolates of Enterobacteriaceae producing Ambler class A and D carbapenemase enzymes and Ambler Class A and C cephalosporinases with an overall MIC90 ≤ 1 mg/L. This, paired with its high absorption and favorable PK profile in humans, make it the optimal oral β-lactam for pairing with the orally bioavailable β-lactamase inhibitor VNRX- 7145.

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