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bioRxiv · 10.1101/2023.02.13.528259

Rapid in vitro activity of telavancin against Bacillus anthracis and in vivo protection against inhalation anthrax infection in the rabbit model

Lawrence, W. S.·Peel, J. E.·Slayden, R.·Peterson, J. W.·Baze, W. B.·Hensel, M. E.·Whorton, E. B.·Beasley, D. W.·Cummings, J. E.·Macias-Perez, I.
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Abstract

Anthrax, caused by the bacterium Bacillus anthracis, is a zoonotic disease that manifests in various forms in human infection, depending on the route of infection. Inhalation anthrax, the most detrimental form of the disease, comes about from the inhalation of anthrax spores and progresses to severe life-threatening conditions late in infection. Notably, there are FDA-approved antibiotics that are effective at treating the disease when administered promptly; however, these antibiotics would be rendered useless against strains of B. anthracis that were genetically modified to be resistant to these antibiotics. Consequently, the search for new and effective therapeutics to combat anthrax infection continues. In this study, telavancin (Vibativ(R)), a semisynthetic lipoglycopeptide antibiotic, was assessed for in vitro activity against 17 B. anthracis strains and tested for the protective efficacy against inhalation anthrax infection in the rabbit model. Telavancin demonstrated potent in vitro activity against B. anthracis which led us to test its efficacy in the rabbit inhalation anthrax model. Rabbits were infected with a lethal dose of anthrax spores via the inhalation route and treated intravenously with telavancin at 30 mg/kg every 12 hours, a dose that mimics the levels measured in the serum of humans, for 5 days upon detection of antigenemia. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals body temperatures were also recorded. Telavancin conveyed 100% survival in this model. Moreover, the dosage of telavancin used for the study effectively cleared B. anthracis from the bloodstream and organ tissues, even more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidal in vivo activity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection. Author SummaryBacillus anthracis, the causative agent of anthrax, continues to interest the research community due to its past and future potential use as bioweapon. Importantly, as a bacterial pathogen, B. anthracis is capable of developing resistance to the antibiotics currently used to treat the infection, either naturally or by deliberate, nefarious means. Consequently, there remains a need to discover, develop, and/or repurpose new antibiotics that would be effective at treating anthrax infection. In this study, we evaluated the antibacterial activity of telavancin, a semisynthetic glycopeptide antibiotic clinically approved to treat complicated skin and skin structure infections, against various strains of B. anthracis in vitro, and we assessed the protective efficacy of telavancin against inhalation anthrax infection in the rabbit model. We show that telavancin is very potent against numerous B. anthracis strains in vitro, and its level of potency surpassed that of another antibiotic currently approved and used to prevent anthrax infection. Moreover, we show that telavancin protects against inhalation anthrax infection in vivo. Overall, our findings support the use of telavancin as an effective therapeutic for anthrax infection.

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Lawrence, W. S., Peel, J. E., Slayden, R., Peterson, J. W., Baze, W. B., Hensel, M. E., Whorton, E. B., Beasley, D. W., Cummings, J. E., Macias-Perez, I.. 2023-02-13. Rapid in vitro activity of telavancin against Bacillus anthracis and in vivo protection against inhalation anthrax infection in the rabbit model. https://doi.org/10.1101/2023.02.13.528259

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