Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

Laura McEntee; Adam Johnson; Nicola Farrington; Jennifer Unsworth; Aaron Dane; Akash Jain; Nicole Cotroneo; Ian Critchley; David Melnick; Thomas Parr; Paul G Ambrose; Shampa Das; William Hope

doi:10.1128/AAC.00603-19

Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00603-19. doi: 10.1128/AAC.00603-19. Print 2019 Aug.

Authors

Affiliations

¹ Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
² DaneStat Consulting, Macclesfield, United Kingdom.
³ Spero Therapeutics, Cambridge, Massachusetts, USA.
⁴ Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
⁵ Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
⁶ Royal Liverpool Broadgreen University Hospital Trust, Liverpool, United Kingdom.

Abstract

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsiella pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC_0-24)/MIC corrected for the length of the dosing interval (fAUC_0-24/MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum β-lactamases versus the wild type. The median fAUC_0-24/MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC_0-24/MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.

Keywords: AMR; ESBL; Gram-negative bacteria; PK-PD; antibiotic resistance; carbapenem; pharmacodynamics; pharmacokinetics; pharmacology; tebipenem.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Anti-Infective Agents / pharmacology*
Carbapenems / pharmacology*
Disease Models, Animal
Drug Resistance, Multiple, Bacterial / drug effects*
Escherichia coli / drug effects
Klebsiella pneumoniae / drug effects
Male
Mice
Microbial Sensitivity Tests
Urinary Tract Infections / drug therapy
Urinary Tract Infections / microbiology

Substances

Anti-Infective Agents
Carbapenems
tebipenem