Evaluation of Tebipenem Hydrolysis by β-Lactamases Prevalent in Complicated Urinary Tract Infections

Area of Science:

• Antimicrobial chemotherapy
• Medicinal chemistry
• Clinical microbiology

Background:

• Tebipenem pivoxil is the first oral carbapenem antibiotic, approved in Japan for pediatric infections.
• Its active form, tebipenem, demonstrates in vitro activity against Enterobacterales from urinary tract infections (UTIs), including those with resistance mechanisms.
• Extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases are key in multidrug-resistant UTIs.

Purpose of the Study:

• To evaluate the stability of tebipenem against clinically relevant β-lactamases.
• To compare the hydrolysis rates of tebipenem with other carbapenems.
• To assess the potential of tebipenem pivoxil for treating adult complicated UTIs (cUTIs).

Main Methods:

• Tebipenem and other carbapenems (imipenem, meropenem, ertapenem) were tested for hydrolysis by TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 β-lactamases.
• Catalytic efficiency (kcat/K) values were determined to quantify hydrolysis rates.

Main Results:

• Tebipenem showed resistance to hydrolysis by TEM-1, CTX-M, and AmpC β-lactamases.
• Tebipenem was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes (kcat/K values: 0.1–2 × 10^6 M⁻¹s⁻¹).
• Results align with observed antimicrobial activity against ESBL/AmpC-producing but not carbapenemase-producing Enterobacterales.

Conclusions:

• Tebipenem's stability against CTX-M and AmpC β-lactamases supports its potential as an oral therapy for adult cUTIs.
• Tebipenem pivoxil hydrobromide (TBP-PI-HBr) may be a valuable oral treatment option for UTIs driven by common resistance mechanisms.