435. Evaluation of Fecal Pharmacokinetics and Metagenomic Changes Following the Administration of Intravenous Omadacycline to Healthy Subjects

Abstract Background Omadacycline (OMC), an aminomethylcycline antibiotic, has potent in vitro activity against C. difficile (CD) and has been associated with a low propensity to cause CD infection when used to treat other infections. A recent phase 1 study of oral OMC demonstrated its protective gut microbiome profile, despite achieving high fecal concentrations, compared to oral vancomycin in healthy subjects. This study aimed to investigate the fecal pharmacokinetics and gut microbiome changes of intravenous (IV) OMC following its administration to healthy volunteers. Methods Healthy adults aged 18 to 40 years consented to receive a 10-day course of OMC: 200 mg of IV on day 1, followed by 100 mg once daily on days 2-5, then 300 mg orally once daily on days 6-10. Daily stool samples were collected and metagenomic analysis targeting 16S ribosomal RNA gene was performed using the Miseq platform (Illumina). Fecal concentrations of OMC were measured using liquid chromatography, mass-spectrometry assay. Results Eight healthy volunteers aged 30±4 years (male: 50%; body mass index: 27.1±4.3 kg/m2) were enrolled. By day 2, 87.5% (7/8) of stool samples had detectable OMC concentrations >40 mcg/g stool, increasing to >100 mcg/g stool by day 5. The maximum OMC concentrations were observed on day 10 (mean 853.5 mcg/g stool). Metagenomic analysis revealed preservation of the Bacteroidota phylum (+0.5±0.3%; p=0.06) and a non-significant increase of the Proteobacteria phylum (+0.9±0.6%; p=0.1). Significant increases were observed in the Actinobacteriota and Verrucomicrobiota phyla (+1.1±0.3%; p< 0.05 and +1.7±0.5%; p< 0.0001, respectively). These changes were driven by the Bifidobacteriaceae and Akkermansiaceae families, respectively. A significant decrease in the Bacillota phylum (-5.1±0.7%; p< 0.0001) was observed, primarily in the Lachnospiraceae, Ruminococcaceae, and Streptococcaceae families. Conclusion Intravenous OMC achieved high fecal concentrations that exceeds the minimum inhibitory concentration 90 of CD while preserving key bacterial species in the gut. Studies investigating changes in bile acids and short-chain fatty acids corresponding with these metagenomic changes are warranted. Disclosures Travis J. Carlson, PharmD, BCIDP, Aimmune Therapeutics, Inc.: Speakers Bureau John C. Williamson, PharmD, Armata Pharmaceuticals: Grant/Research Support|Blue Collar Vaccines and Therapeutics: Board Member|Blue Collar Vaccines and Therapeutics: Ownership Interest|Paratek Pharmaceuticals: Grant/Research Support|ST Pharm Co, Ltd: Grant/Research Support Anne J. Gonzales-Luna, PharmD, BCIDP, Ferring Pharmaceuticals: Advisor/Consultant|Innoviva Specialty Therapeutics: Advisor/Consultant|Merck and Co: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin W. Garey, MS;PharmD, Paratek Pharmaceuticals: Grant/Research Support