Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax

Abstract

Although antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P=0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n=39) than for LVX alone (13 deaths; n=37), and the survival time was prolonged for the combination (P=0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course.

FIG 1

Survival outcomes in New Zealand White rabbits after challenge with B. anthracis spores at ∼200 times the LD₅₀ and treatment with LVX (50 mg/kg daily for 3 days) plus a single i.v. dose of placebo or 40 mg/kg raxibacumab administered at 84 h postchallenge. (A) Primary endpoint analysis. The P value is based on a two-sided likelihood-ratio chi-square test. (B) Absolute improvement in day 28 survival by subgroup and 95% CI for the raxibacumab-LVX combination group compared with the LVX-alone group. X, point estimate; solid vertical line, 0% benefit; dashed vertical line, point estimate of the survival benefit in the overall (ITT) population. The 95% CIs were calculated by normal approximation. levo, levofloxacin; raxi, raxibacumab. (C) Survival time from the time of spore challenge. The P value was obtained from a log-rank test comparing the survival times between the raxibacumab-LVX combination group and the LVX-alone group.

FIG 2

Plasma raxibacumab concentration-time profiles in rabbits administered 3 daily intragastric 50-mg/kg LVX doses in combination with a single i.v. 40-mg/kg raxibacumab dose. (Top) Linear scale; (bottom) semilogarithmic scale.