title: In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline.
abstract: Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively, and the omadacycline MIC90s for PRSP and H. influenzae were 0.25 μg/ml and 2.0 μg/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet(M) and tet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s for Staphylococcus aureus obtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli was 2.02 mg/kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo.
authors.affiliation: Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Macone
authors.forename: B K
authors.initials: BK
authors.lastname: Caruso
authors.forename: R G
authors.initials: RG
authors.lastname: Leahy
authors.forename: J
authors.initials: J
authors.lastname: Donatelli
authors.forename: S
authors.initials: S
authors.lastname: Weir
authors.forename: M P
authors.initials: MP
authors.lastname: Draper
authors.forename: S K
authors.initials: SK
authors.lastname: Tanaka
authors.forename: S B
authors.initials: SB
authors.lastname: Levy
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D016983:Enterococcus / Q000187:drug effects* / Q000254:growth & development; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D015870:Gene Expression; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000254:growth & development; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests; D010537:Peritoneum / Q000187:drug effects / Q000382:microbiology; D012270:Ribosomes / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development; D013754:Tetracyclines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D013754:Tetracyclines; C000591640:omadacycline