Combination therapy with antibiotics and anthrax immune globulin intravenous (AIGIV) is potentially more effective than antibiotics alone in rabbit model of inhalational anthrax.

BACKGROUND: We have evaluated the therapeutic efficacy of AIGIV when given in combination with levofloxacin and the effective window of treatment to assess the added benefit provided by AIGIV over standard antibiotic treatment alone in a New Zealand white rabbit model of inhalational anthrax. METHODS: Rabbits were exposed to lethal dose of aerosolized spores of Bacillus anthracis (Ames strain) and treated intravenously with either placebo, (normal immune globulin intravenous, IGIV) or 15 U/kg of AIGIV, along with oral levofloxacin treatment at various time points (30-96 hours) after anthrax exposure. RESULTS: The majority of treated animals (>88%) survived in both treatment groups when treatment was initiated within 60 hours of post-exposure. However, reduced survival of 55%, 33% and 25% was observed for placebo + levofloxacin group when the treatment was initiated at 72, 84 and 96 hours post-exposure, respectively. Conversely, a survival rate of 65%, 40% and 71% was observed in the AIGIV + levofloxacin treated groups at these time points. CONCLUSIONS: The combination of AIGIV with antibiotics provided an improvement in survival compared to levofloxacin treatment alone when treatment was delayed up to 96 hours post-anthrax exposure. Additionally, AIGIV treatment when given as an adjunct therapy at any of the time points tested did not interfere with the efficacy of levofloxacin

Pre-Treatment (Post-Challenge) and Post-Treatment Mean PA levels in Sera from Study 1 Rabbits.

<p>New Zealand white rabbits were exposed to 200×LD₅₀ doses of aerosolized <i>B. anthracis</i> spores and serum collected at different time points Post-Challenge (A) and Post-Infusion (B) was tested by electro-chemiluminiscence (ECL) assay for detection and quantitation of <i>B. anthracis</i> protective antigen (PA). Animals received combination treatment with Placebo+ levofloxacin or AIGIV + levofloxacin at 30, 36, 48 and 60 hours post-exposure. AIGIV was given IV as a slow infusion at 15 U/kg of body weight and levofloxacin at 50 mg/kg given orally once a day for 3 days. PI = Post-Infusion PC = Post-Challenge.</p

Summary of mean time to death and survival of rabbits in two sequential combination treatment studies.

1<p>Survival rates for each group at day 30 post exposure.</p>2<p>Time-to-death and overall survival rates between groups by pairwise Log-rank test. NA- Log-rank test was not possible due to no deaths occurred in either group.</p>3<p>A total of 9 animals were exposed to anthrax spores but two were excluded from survival analysis due to death related to gavage error. - Not determined due to lack of sufficient number of deaths.</p>4<p>Survival rates for each group at day 32 post exposure.</p>5<p>Comparing overall-survival between the groups. *Two animals from 72 hours and one animal from 84 hours group were non bacteremic at the time of treatment.</p><p>Summary of mean time to death and survival of rabbits in two sequential combination treatment studies.</p

Post-Treatment Mean PA levels in Sera from Study 2 Rabbits.

<p>Animals received combination treatment with Placebo+ levofloxacin or AIGIV + levofloxacin at 60, 72, 84 and 96 hour post-exposure. AIGIV was given IV as a slow infusion at 15 U/kg of body weight and levofloxacin at 50 mg/kg given orally once a day for 3 days. The levels of PA were significantly reduced (P<0.05; ANOVA model and Wilcoxon rank sum test) following treatment with AIGIV and levofloxacin compared to treatment with IGIV and levofloxacin. PI = Post-Infusion PC = Post-Challenge.</p

Effect of combination treatment on incidence of bacteremia and toxemia in study 1.

<p>NA- not applicable as animals were not treated.** data from all time points up to treatment (pre-treatment) and all time points post-treatment were combined for overall incidence.</p><p>Effect of combination treatment on incidence of bacteremia and toxemia in study 1.</p

Effect of combination treatment on incidence of bacteremia in study 2.

a<p> The overall mean onset time for all groups is 31.54 (19.50, 85.37).</p>b<p> Pairwise comparison Fisher's exact test p>0.05 AIGIV+levofloxacin vs. placebo+levofloxacin.</p><p>— No animal died.</p><p>**Post-treatment blood collection was relative to the end of infusion (after the first levofloxacin dose).</p><p>Effect of combination treatment on incidence of bacteremia in study 2.</p