Omadacycline is an aminomethylcycline (tetracycline class) antibacterial approved by the US Food and Drug Administration in 2018 for the treatment of indicated organism groups and is available as intravenous and oral formulations. Omadacycline activity was assessed against 35,000 bacterial clinical isolates from medical centers in the United States (2019-2023) as part of the 5-year post-marketing surveillance commitment. Applying United States Food and Drug Administration breakpoint interpretive criteria, 98.2% of Staphylococcus aureus (including 96.1% of methicillin-resistant strains), 99.3% of Staphylococcus lugdunensis, 99.9% of Streptococcus pneumoniae, 99.4% of Streptococcus pyogenes, 99.9% of Enterococcus faecalis, 99.9% of Haemophilus influenzae, 92.4% of Enterobacter cloacae, and 92.5% of Klebsiella pneumoniae isolates were susceptible to omadacycline. Omadacycline demonstrated consistent potent activity across the 5-year post-marketing surveillance program against key indicated organism groups and resistant organism subsets. These results demonstrate that omadacycline may merit further consideration for the treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community Acquired Bacterial Pneumonia (CABP) as well as further study in the treatment of serious infections where resistant pathogens may be encountered, infections which lack currently available treatments, or where an oral treatment option is desired.