In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens

Abstract

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei 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 in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 μg/ml for B. anthracis, ≤0.0005 - 0.03 μg/ml for Y. pestis, 0.25 - 1 μg/ml for B. mallei, and 1 - 4 μg/ml for B. pseudomallei In a B. anthracis 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 Y. pestis, 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.

FIG 1

Kaplan-Meier analysis of mouse survival up to 28 days after challenge with Bacillus anthracis Ames and treatment with tebipenem (TBP) or ciprofloxacin, as indicated. N/A, not applicable; pc, postchallenge.

FIG 2

Composite concentration-time curve for tebipenem in mouse plasma on day 1 (group 8) and day 14 (group 9) for Bacillus anthracis Ames-challenged mice.

FIG 3

Kaplan-Meier analysis of mouse survival up to 28 days after challenge with Yersinia pestis CO92 and treatment with tebipenem (TBP) or ciprofloxacin, as indicated. pc, postchallenge.

FIG 4

Composite concentration-time curve for tebipenem in mouse plasma on day 1 (group 8) and day 14 (group 9) for Yersinia pestis CO92-challenged mice.