The Class A β-Lactamase Produced by Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States.

Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, and . Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of complex (Bcc) and , pathogens that infect people who are immunocompromised or have cystic fibrosis. Using the provisional susceptibility breakpoint of 0.12 mg/L for tebipenem, 100% of the Bcc and . tested as being provisionally resistant to tebipenem. Bcc and . possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a / value of 1.9 ± 0.1 × 10 Ms. In addition, tebipenem was found to be a weak inducer of expression. The combination of the slow hydrolysis by PenA1 and weak induction of likely compromises the potency of tebipenem against Bcc and . .