Omadacycline is active <i>in vitro</i> and <i>in vivo</i> against ciprofloxacin-resistant <i>Bacillus anthracis</i>

<i>Bacillus anthracis</i>, the causative agent of anthrax, is among the most likely bacterial pathogens to be used in a biological attack. Inhalation anthrax is a serious, life-threatening form of infection, and the mortality from acute inhaled anthrax can approach 100% if not treated early and aggressively. Food and Drug Administration-approved antibiotics indicated for post-exposure prophylaxis (PEP) or treatment of anthrax are limited. This study assessed the <i>in vitro</i> activity and <i>in vivo</i> efficacy of omadacycline and comparators against clinical isolates of <i>B. anthracis,</i> including a ciprofloxacin-resistant isolate. Minimum inhibitory concentrations (MICs) of omadacycline, ciprofloxacin, and doxycycline were determined against animal and human clinical isolates of <i>B. anthracis</i>, including the ciprofloxacin-resistant Ames strain BAC^r4-2. Mice were challenged with aerosolized BAC^r4-2 spores, and survival was monitored for 28 days post-challenge. Treatment was initiated 24 h after aerosol challenge and administered for 14 days. Omadacycline demonstrated <i>in vitro</i> activity against 53 <i>B. anthracis</i> isolates with an MIC range of ≤0.008-0.25 µg/mL, and an MIC₅₀/MIC₉₀ of 0.015/0.03 µg/mL. Consistent with this, omadacycline demonstrated <i>in vivo</i> efficacy in a PEP mouse model of inhalation anthrax caused by the Ames BAC^r4-2 ciprofloxacin-resistant <i>B. anthracis</i> isolate. Omadacycline treatment significantly increased survival compared with the vehicle control group and the ciprofloxacin treatment group. As antibiotic resistance rates continue to rise worldwide, omadacycline may offer an alternative PEP or treatment option against inhalation anthrax, including anthrax caused by antibiotic-resistant <i>B. anthracis</i>.