title: In VivoPharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model.
abstract: Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize thein vivopharmacodynamic activity of omadacycline againstStreptococcus pneumoniaeFour strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R2= 0.74). The plasma 24-h static dose AUC/MIC values were 16 to 20 (24-h ELF AUC/MIC of 14 to 18). A 1-log10kill was achieved at 24-h plasma AUC/MIC values of 6.1 to 180 (24-h ELF AUC/MIC values 6.0 to 200). A 2-log10kill was achieved at 24-h plasma AUC/MIC values of 19 to 56 (24-h ELF AUC/MIC of 17 to 47). The targets identified in this study in combination within vitropotency and favorable human pharmacokinetics make omadacycline an attractive candidate for further development and study in patients with CABP.
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lepak
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhao
authors.affiliation: William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Marchillo
authors.affiliation: William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: VanHecker
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA dra@medicine.wisc.edu.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.|William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013754:Tetracyclines / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D013754:Tetracyclines; C000591640:omadacycline
keywords: omadacycline; pharmacodynamics; pneumonia