Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections
Autor: | Laura McEntee, William W. Hope, Aaron Dane, Akash Jain, Jennifer Unsworth, Ian A. Critchley, Nicola Farrington, Shampa Das, Nicole Cotroneo, David Melnick, Adam Johnson, Thomas R. Parr, Paul G. Ambrose |
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Rok vydání: | 2019 |
Předmět: |
Male
Carbapenem Klebsiella pneumoniae Tebipenem Administration Oral Microbial Sensitivity Tests Pharmacology 03 medical and health sciences chemistry.chemical_compound Mice Antibiotic resistance Pharmacokinetics Anti-Infective Agents Drug Resistance Multiple Bacterial medicine Escherichia coli Animals Pharmacology (medical) PK/PD models 030304 developmental biology 0303 health sciences biology 030306 microbiology business.industry biology.organism_classification Multiple drug resistance Disease Models Animal Infectious Diseases chemistry Carbapenems Pharmacodynamics Urinary Tract Infections business medicine.drug |
Zdroj: | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY |
ISSN: | 1098-6596 |
Popis: | 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. |
Databáze: | OpenAIRE |
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