In Vitro and In Vivo Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis

Abstract

The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis. The in vivo efficacy 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 active in vitro against Y. pestis (MIC90 of 1 μg/ml) and B. anthracis (MIC90 of 0.06 μg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 μg/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 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 aerosolized B. anthracis. Additionally, for postexposure prophylaxis treatment of mice infected with Y. 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 both B. anthracis and Y. pestis. The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.

Omadacycline Enters the Ring: A New Antimicrobial Contender

“…Reduced susceptibility to all tetracyclines was observed for Eikenella spp. Omadacycline activity has also been evaluated against bioterrorism pathogens, including Bacillus anthracis and Yersinia pestis . The MIC 90 value observed for omadacycline for B. anthracis was 0.06 mg/L compared to 0.06 mg/L for doxycycline and 0.12 mg/L for both ciprofloxacin and tetracycline.…”

“…Two distinct animal efficacy models of omadacycline have been described . First, omadacycline was evaluated against four strains of S. pneumoniae (MIC 0.03–0.125 mg/L) in a murine pneumonia model .…”

“…In the Yersinia arm, animals were exposed to three separate doses of Y. pestis (mean 29.4x LD 50 ) by whole‐body aerosol . Omadacycline (5–40 mg/kg IP twice/day) for 7 days was compared to doxycycline (5–40 mg/kg twice/day), ciprofloxacin (15 mg/kg twice/day), and saline.…”

“…Two distinct animal efficacy models of omadacycline have been described. 14,24 First, omadacycline was evaluated against four strains of S. pneumoniae (MIC 0.03-0.125 mg/L) in a murine pneumonia model. 24 Omadacycline was administered subcutaneously at doses ranging from 0.1 to 25.6 mg/kg every 12 hours and was bactericidal at all doses in two strains.…”

“…14 In the Bacillus PEP arm, animals were exposed to four separate doses of B. anthracis (mean 30.5 9 50% lethal dose [LD 50 ]) by whole-body aerosol. 14 Omadacycline was administered 24 hours postexposure at doses ranging from 0.75 to 15 mg/kg IP twice/day and was compared to ciprofloxacin 30 mg/kg twice/day, doxycycline 0.75-15 mg/kg twice/day, and saline. Omadacycline-and doxycycline-matched doses (2.5-15 mg/kg) demonstrated similar survival rates, but omadacycline 0.75 mg/ kg-dose survival was significantly better (p=0.0125).…”