The Class A β-Lactamase Produced by Burkholderia 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, Burkholderia pseudomallei and Burkholderia mallei . Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of Burkholderia cepacia complex (Bcc) and Burkholderia gladioli , 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 B . gladioli tested as being provisionally resistant to tebipenem. Bcc and B . gladioli possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in Burkholderia multivorans ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a k 2 / K value of 1.9 ± 0.1 × 10 3 M -1 s -1 . In addition, tebipenem was found to be a weak inducer of bla PenA1 expression. The combination of the slow hydrolysis by PenA1 and weak induction of bla PenA1 likely compromises the potency of tebipenem against Bcc and B . gladioli .