Synergistic effect of the novel beta-lactamase inhibitor BLI-489 combined with imipenem or meropenem against diverse carbapenemase-producing carbapenem-resistant Enterobacterales

Objectives To investigate the antibacterial activity of the novel beta-lactamase inhibitor BLI-489 combined with imipenem or meropenem against diverse carbapenemase-producing carbapenem-resistant Enterobacterales (CRE) in vivo and in vitro. Methods Twenty-five CRE strains, including Klebsiella pneumoniae (n = 10), Escherichia coli (n = 6) and Enterobacter cloacae (n = 9), were used in chequerboard assays to evaluate the synergistic effect of BLI-489 combined with imipenem or meropenem. A cytotoxicity test was used to detect the toxicity of BLI-489 monotherapy or combination therapy. Three isolates producing class A, B and D carbapenemases, respectively, were selected to further confirm the synergistic effect in vitro by time-kill assays and in vivo by the Galleria mellonella infection model. Results Chequerboard assays demonstrated that BLI-489 combined with imipenem had a synergistic effect on 7/10, 7/9 and 5/6 of carbapenem-resistant K. pneumoniae, E. cloacae and E. coli, respectively, while BLI-489 and meropenem had a synergistic effect on 8/10, 9/9 and 6/6 of the isolates, respectively. No cytotoxicity was observed when BLI-489 was used alone or in combination with imipenem or meropenem at the test concentrations. In the time-kill assays, combination therapy had a synergistic effect on DC5114 carrying bla(KPC-2), FK8401 carrying bla(NDM-5) and CG996 carrying bla(OXA-23). The synergistic effect in vivo was confirmed by the G. mellonella infection model. Conclusions The novel beta-lactamase inhibitor BLI-489 possesses a synergistic effect against diverse carbapenemase-producing CRE combined with imipenem or meropenem.