Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii

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 (MIC₉₀ values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC₉₀ 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 MIC₉₀ 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.

Keywords: A. baumannii; ANT3310; carbapenem-resistance; meropenem; β-lactamase inhibitor.

Fig 1

Cumulative MIC distribution of MEM-ANT3310 (8 µg/mL) against (A) 905 A. baumannii and (B) 703 CRAB clinical isolates (2018/2019 IHMA collections).

Fig 2

Cumulative MIC distribution of MEM-ANT3310 (8 µg/mL) and other BL/BLI combinations against A. baumannii or CRAB global isolates from (A) and (C) year 2018 collection (n = 500 and n = 363, respectively) and (B) and (D) year 2019 collection (n = 405 and n = 340, respectively).

Fig 3

Cumulative MIC distribution of MEM-ANT3310 (8 µg/mL) and other BL/BLI combinations against (A) OXA-CRE (n = 252) and (B) KPC-CRE (n = 180) from the 2018 global collection.

Fig 4

Cumulative MIC distribution of MEM, MEM-ANT3310 (8 µg/mL), and other BL/BLI combinations against 502 P. aeruginosa.

Fig 5

In vivo efficacy of MEM and MEM-ANT3310 against OXA-23 A. baumannii in murine (A) thigh and (B) lung infection models. MEM, MEM-ANT3310, and TIG MICs against this isolate are, respectively, 64, 4, and 2 µg/mL.