Evaluation of Combination Drug Therapy for Treatment of Antibiotic Resistant Inhalation Anthrax in a Murine Model [PublishAheadOfPrint]

Bacillus anthracis is considered a likely agent to be used as a bioweapon and use of a strain resistance to the first-line antimicrobial treatments is a concern. We determined treatment efficacy against a ciprofloxacin-resistant (C^r) strain of B. anthracis (C^r Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7-35 LD₅₀ of B. anthracis C^r Ames spores. Commencing at 36 hours (h) post-exposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacinalone (control groups), or ciprofloxacin combined with two antimicrobials including meropenem/linezolid, meropenem/clindamycin, meropenem/rifampin, meropenem/doxycycline, penicillin/linezolid, penicillin/doxycycline, rifampin/linezolid, or rifampin/clindamycin at appropriate dosing intervals(6 or 12 hours) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. Remaining animals were euthanized every 6-12h and blood, lungs, and spleens collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem/linezolid (p=0.004), meropenem/clindamycin (p=0.005), meropenem/rifampin (p=0.012), meropenem/doxycycline (p=0.032), penicillin/doxycycline (p=0.012), penicillin/linezolid (p=0.026), rifampin/linezolid (p=0.001), and rifampin/clindamycin (p=0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24 hours treatment. LF fell below detection limits for all combination groups, yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.

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