In Vitro and In Vivo Characterization of Tebipenem, 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.

Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018–2020 Global Surveillance Collection

“…These results were comparable to those for imipenem-relebactam (86.5% susceptible at the CLSI breakpoint and 91.9% susceptible at the EUCAST breakpoint). Meropenem (84.6% susceptible [CLSI] and 86.5% susceptible [EUCAST]) and imipenem (77.6% and 85.2%) were slightly less active than ceftibuten-ledaborbactam against MDR isolates; 72.0% of MDR isolates were susceptible to tebipenem at its provisional susceptible breakpoint of ≤0.12 μg/mL ( 16 ). Using CLSI investigational MIC breakpoints for ceftibuten (susceptible, ≤8 μg/mL; intermediate 16 μg/mL; resistant, ≥32 μg/mL) ( 15 ), ceftibuten alone was 25 to 30% less active (reflecting less susceptibility) than ceftibuten-ledaborbactam against MDR isolates.…”

“…For cefepime, percentages in the intermediate column are isolates that tested with a susceptible–dose-dependent MIC (4 to 8 μg/mL). j A provisional susceptibility breakpoint of ≤0.12 μg/mL was applied for tebipenem ( 16 ). k ESBL phenotype isolates were defined as isolates of E. coli , K. pneumoniae , K. oxytoca , and P. mirabilis with ceftazidime MICs of ≥2 μg/mL and meropenem MICs of ≤1 μg/mL.…”

“…For cefepime, percentages in the intermediate column are isolates that tested with a susceptible–dose-dependent MIC (4 to 8 μg/mL). i A provisional susceptible breakpoint of ≤0.12 μg/mL was applied for tebipenem ( 16 ). …”

“…For comparative purposes, ceftibuten-ledaborbactam MICs were interpreted using two provisional susceptibility breakpoints, ≤1 μg/mL and ≤0.5 μg/mL. Tebipenem MICs were interpreted using a provisional susceptibility breakpoint of ≤0.12 μg/mL ( 16 ).…”

Efficacy of ANTHRASIL (Anthrax Immune Globulin Intravenous (Human)) in rabbit and nonhuman primate models of inhalational anthrax: Data supporting approval under animal rule

“…All aerosol challenges occurred with a well-characterized, single lot of B. anthracis (Ames strain) spores [44]. Characterization involved percentage encapsulation (pXO1/pXO2 gene expression), colony morphology on blood agar, microscopic observation for culture purity, percentage spore refractility, Guinea pig LD 50 and spray factor.…”