In vitro activity of combination formulations of the novel metallo-β-lactamase (MBL) inhibitor APC148 with comparator treatments against 176 MBL-containing Enterobacterales isolates from the SENTRY Antimicrobial Surveillance Program (2019-2022)

The global dissemination of Enterobacterales producing both metallo-β-lactamases (MBLs) and serine β-lactamases (SBLs) represents a critical threat to modern medicine, as no currently marketed antibiotics effectively target MBL-mediated resistance. APC148 is a novel, selective zinc-chelating MBL inhibitor designed to restore β-lactam activity in MBL positive isolates, when used in combination with a broad-spectrum carbapenem. In this study, we evaluated the in vitro efficacy of APC148 in triple combinations with either meropenem-avibactam (APC301) or cefepime-avibactam (APC302) against a diverse global collection (JMI collection) of 176 MBL- and SBL-producing Enterobacterales isolates (including NDM, VIM, and IMP variants). Using broth microdilution, the triple combinations were compared against several newly approved and late-stage pipeline antibiotic products. Both APC301 and APC302 demonstrated superior potency, achieving a MIC 90 of 0.12 µg/mL. When applying CLSI breakpoint interpretive criteria for the parent β-lactams, 99.4% of the MBL and SBL-containing isolates were susceptible to APC301, while 97.2% were susceptible to APC302. These results indicate that the addition of a selective MBL inhibitor to an SBL-inhibitor/β-lactam antibiotic effectively bypasses complex co-existing β-lactam resistance mechanisms in multidrug-resistant (MDR) pathogens. Given that MDR Enterobacterales frequently harbor multiple β-lactamase classes simultaneously, these triple combinations constitute a highly promising clinical strategy to address the therapeutic void in MBL-mediated resistance