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

McEntee, Laura, Johnson, Adam ORCID: 0000-0002-6684-3321, Farrington, Nicola, Unsworth, Jennifer, Dane, Aaron, Jain, Akash, Cotroneo, Nicole, Critchley, Ian, Melnick, David, Parr, Thomas
et al (show 3 more authors) (2019) Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 63 (8). e00603-e00619.

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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 <i>Enterobacteriaceae</i> (<i>Escherichia coli</i>, <i>n</i> = 6; <i>Klebsiella pneumoniae</i>, <i>n</i> = 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 (<i>f</i>AUC<sub>0-24</sub>)/MIC corrected for the length of the dosing interval (<i>f</i>AUC<sub>0-24</sub>/MIC · 1/tau). The pharmacodynamics of tebipenem versus <i>E. coli</i> and <i>K. pneumoniae</i> were comparable, as was the response of strains possessing extended-spectrum β-lactamases versus the wild type. The median <i>f</i>AUC<sub>0-24</sub>/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 <i>f</i>AUC<sub>0-24</sub>/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.

Item Type: Article
Uncontrolled Keywords: AMR, ESBL, Gram-negative bacteria, PK-PD, antibiotic resistance, carbapenem, pharmacodynamics, pharmacokinetics, pharmacology, tebipenem
Depositing User: Symplectic Admin
Date Deposited: 04 Jun 2019 07:28
Last Modified: 24 Jan 2024 23:55
DOI: 10.1128/AAC.00603-19
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