The Class A β-Lactamase Produced by <i>Burkholderia</i> Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States

• Main Authors: Scott A. Becka (Author), Elise T. Zeiser (Author), John J. LiPuma (Author), Krisztina M. Papp-Wallace (Author)
• Format: Book
• Published: MDPI AG, 2022-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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, <i>Burkholderia pseudomallei</i> and <i>Burkholderia mallei</i>. Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of <i>Burkholderia cepacia</i> complex (Bcc) and <i>Burkholderia gladioli</i>, 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 <i>B</i>. <i>gladioli</i> tested as being provisionally resistant to tebipenem. Bcc and <i>B</i>. <i>gladioli</i> possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in <i>Burkholderia multivorans</i> ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a <i>k</i>₂/<i>K</i> value of 1.9 ± 0.1 × 10³ M⁻¹s⁻¹. In addition, tebipenem was found to be a weak inducer of <i>bla</i>_PenA1 expression. The combination of the slow hydrolysis by PenA1 and weak induction of <i>bla</i>_PenA1 likely compromises the potency of tebipenem against Bcc and <i>B</i>. <i>gladioli</i>.

Item Description

10.3390/antibiotics11050674
2079-6382