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The impact of Actotoxumab treatment of gnotobiotic piglets infected with different Clostridium difficile isogenic mutants.

Abstract

Nosocomial infections with Clostridium difficile are on the rise in the USA, attributed to emergence of antibiotic resistant and hypervirulent strains associated with greater likelihood of recurrent infections. In addition to antibiotics, treatment with Merck anti-TcdB antibody Bezlotoxumab reported to reduce recurrent infections. However, treatment with anti-TcdA antibody Actotoxumab had dramatically increased disease severity and mortality rates in humans and gnotobiotic piglets. Utilizing isogenic mutants of C. difficile strain NAPI/BI/027 deficient in TcdA (A-B+) or TcdB (A+B-), and the WT, we investigated how/why treatment with anti-TcdA of infected animals dramatically increased disease severity. Contrary to the hypothesis, A+B- infected piglets treated with anti-TcdA were disease free, compared to disease enhancement with anti-TcdA treated WT or A-B+. It appears the lack of TcdA, either through deletion or neutralization with anti-TcdA, reduces a competitive pressure allowing TcdB to freely exert its profound effect leading to increased mucosal injury and disease severity.

Authors+Show Affiliations

Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.Department of Infectious Diseases and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31495879

Citation

Danz, Hillary R., et al. "The Impact of Actotoxumab Treatment of Gnotobiotic Piglets Infected With Different Clostridium Difficile Isogenic Mutants." The Journal of Infectious Diseases, 2019.
Danz HR, Lee S, Chapman-Bonofiglio SP, et al. The impact of Actotoxumab treatment of gnotobiotic piglets infected with different Clostridium difficile isogenic mutants. J Infect Dis. 2019.
Danz, H. R., Lee, S., Chapman-Bonofiglio, S. P., Ginese, M., Beamer, G., Girouard, D. J., & Tzipori, S. (2019). The impact of Actotoxumab treatment of gnotobiotic piglets infected with different Clostridium difficile isogenic mutants. The Journal of Infectious Diseases, doi:10.1093/infdis/jiz459.
Danz HR, et al. The Impact of Actotoxumab Treatment of Gnotobiotic Piglets Infected With Different Clostridium Difficile Isogenic Mutants. J Infect Dis. 2019 Sep 9; PubMed PMID: 31495879.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The impact of Actotoxumab treatment of gnotobiotic piglets infected with different Clostridium difficile isogenic mutants. AU - Danz,Hillary R, AU - Lee,Sangun, AU - Chapman-Bonofiglio,Susan P, AU - Ginese,Melanie, AU - Beamer,Gillian, AU - Girouard,Donald J, AU - Tzipori,Saul, Y1 - 2019/09/09/ PY - 2019/05/17/received PY - 2019/9/10/entrez KW - Clostridium difficile KW - Actotoxumab KW - gnotobiotic piglets KW - isogenic mutant JF - The Journal of infectious diseases JO - J. Infect. Dis. N2 - Nosocomial infections with Clostridium difficile are on the rise in the USA, attributed to emergence of antibiotic resistant and hypervirulent strains associated with greater likelihood of recurrent infections. In addition to antibiotics, treatment with Merck anti-TcdB antibody Bezlotoxumab reported to reduce recurrent infections. However, treatment with anti-TcdA antibody Actotoxumab had dramatically increased disease severity and mortality rates in humans and gnotobiotic piglets. Utilizing isogenic mutants of C. difficile strain NAPI/BI/027 deficient in TcdA (A-B+) or TcdB (A+B-), and the WT, we investigated how/why treatment with anti-TcdA of infected animals dramatically increased disease severity. Contrary to the hypothesis, A+B- infected piglets treated with anti-TcdA were disease free, compared to disease enhancement with anti-TcdA treated WT or A-B+. It appears the lack of TcdA, either through deletion or neutralization with anti-TcdA, reduces a competitive pressure allowing TcdB to freely exert its profound effect leading to increased mucosal injury and disease severity. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/31495879/The_impact_of_Actotoxumab_treatment_of_gnotobiotic_piglets_infected_with_different_Clostridium_difficile_isogenic_mutants L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiz459 DB - PRIME DP - Unbound Medicine ER -