title: In VitroandIn VivoActivity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis.
abstract: Thein vitroactivity andin vivoefficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague,Bacillus anthracisandYersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each ofY. pestisandB. anthracisThein vivoefficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was activein vitroagainstY. pestis(MIC90of 1 μg/ml) andB. anthracis(MIC90of 0.06 μg/ml). Omadacycline was less activein vitrothan ciprofloxacin (CIP) againstY. pestis(CIP MIC90of 0.03 μg/ml) but was more potentin vitroagainstB. anthracis(CIP MIC90of 0.12 μg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (P= 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolizedB. anthracisAdditionally, for postexposure prophylaxis treatment of mice infected withY. pestis, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (P< 0.0001). Omadacycline is potent and demonstrates efficacy against bothB. anthracisandY. pestisThe well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.
authors.affiliation: Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA Judith.steenbergen@paratekpharma.com.
authors.forename: Judith
authors.initials: J
authors.lastname: Steenbergen
authors.affiliation: Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors.forename: S Ken
authors.initials: SK
authors.lastname: Tanaka
authors.affiliation: Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors.forename: Lynda L
authors.initials: LL
authors.lastname: Miller
authors.affiliation: Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Halasohoris
authors.affiliation: Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Hershfield
mesh_terms: D000336:Aerosols; D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000382:microbiology; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001408:Bacillus anthracis / Q000187:drug effects*; D054045:Biological Warfare Agents; D002939:Ciprofloxacin / Q000627:therapeutic use; D004318:Doxycycline / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010930:Plague / Q000188:drug therapy* / Q000382:microbiology; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D013754:Tetracyclines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015010:Yersinia pestis / Q000187:drug effects*
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D054045:Biological Warfare Agents; D013754:Tetracyclines; C000591640:omadacycline; D002939:Ciprofloxacin; D004318:Doxycycline
keywords: anthrax; biothreat; omadacycline