Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant <i>Acinetobacter baumannii</i>
Magdalena Zalacaín, Pauline Achard, Agustina Llanos, Ian Morrissey, Stephen Hawser, Kirsty Holden, Eleanor Toomey, David T. Davies, Simon Leiris, Carole A. Sable, Adeline Ledoux, Justine Bousquet, Jérôme Castandet, Clarisse Lozano, Martin Everett, Marc Lemonnier
Abstract
ABSTRACT ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii ( n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) ( n = 252) or Klebsiella pneumoniae carbapenemase (KPC) ( n = 180) carbapenemases, and Pseudomonas aeruginosa ( n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC 90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC 90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC 90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii . This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations.