In Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance Mechanisms

Abstract

QPX7728 is an investigational ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed 1-16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales. The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo beta-lactamases (151 NDM, 53 VIM, 20 IMP) and 50 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porin genes, OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of meropenem against CRE, with the meropenem MIC₉₀ decreasing from >64 mg/ml to 0.5 μg/mL for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of meropenem against CRE with multiple resistance mechanisms; the reduction in meropenem MIC₉₀ with QPX7728 (8 μg/ml) ranged from 32 to >256-fold. Compared with other beta-lactamase inhibitor combinations meropenem-vaborbactam, ceftazidime-avibactam, or imipenem-relebactam, meropenem with QPX7728 was the most potent beta-lactam/BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of meropenem with vaborbactam (128 -fold decrease in MIC₉₀) whereas only a 8-16-fold change was observed with QPX7728 plus meropenem. >90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of meropenem with QPX7728 at 8 μg/ml or less. The combination of QPX7728 with meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.