In VitroandIn VivoAntibacterial Activities of Omadacycline, a Novel Aminomethylcycline

Abstract

ABSTRACTOmadacycline 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 comparativein vitroactivity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-resistantEnterococcus(VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistantStreptococcus pneumoniae(PRSP), andHaemophilus 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 andH. influenzaewere 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 vivoefficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy againstStreptococcus pneumoniae,Escherichia coli, andStaphylococcus aureus, includingtet(M) andtet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) forStreptococcus pneumoniaeobtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s forStaphylococcus aureusobtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50forEscherichia coliwas 2.02 mg/kg. These results demonstrate potentin vivoefficacy including activity against strains containing common resistance determinants. Omadacycline demonstratedin vitroactivity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacyin vivo.