<i>In Vitro</i> and <i>In Vivo</i> Characterization of Tebipenem, an Orally Active Carbapenem, against Biothreat Pathogens

Abstract

<i>Bacillus anthracis</i> and <i>Yersinia pestis</i>, causative pathogens for anthrax and plague, respectively, along with <i>Burkholderia mallei</i> and <i>B. pseudomallei</i> are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the <i>in vitro</i> activity and <i>in vivo</i> efficacy of tebipenem against biothreat pathogens. Tebipenem was active <i>in vitro</i> against 30-strain diversity sets of <i>B. anthracis</i>, <i>Y. pestis</i>, <i>B. mallei,</i> and <i>B. pseudomallei</i> with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 μg/ml for <i>B. anthracis</i>, ≤0.0005 - 0.03 μg/ml for <i>Y. pestis</i>, 0.25 - 1 μg/ml for <i>B. mallei</i>, and 1 - 4 μg/ml for <i>B. pseudomallei</i> In a <i>B. anthracis</i> murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For <i>Y. pestis,</i> survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.