The Impact of Actotoxumab Treatment of Gnotobiotic Piglets Infected With Different Clostridium difficile Isogenic Mutants
January 15, 2020
Danz HR, Lee S, Chapman-Bonofiglio SP, Ginese M, Beamer G, Girouard DJ, Tzipori S.
J Infect Dis. 2020 Jan 2;221(2):276-284.
PMID: 31495879 | DOI: 10.1093/infdis/jiz459
Nosocomial infections with Clostridium difficile are on the rise in the Unites States, attributed to emergence of antibiotic-resistant and hypervirulent strains associated with greater likelihood of recurrent infections. In addition to antibiotics, treatment with Merck anti-toxin B (TcdB) antibody bezlotoxumab is reported to reduce recurrent infections. However, treatment with anti-toxin A (TcdA) antibody actotoxumab was associated with dramatically increased disease severity and mortality rates in humans and gnotobiotic piglets. Using isogenic mutants of C. difficile strain NAPI/BI/027 deficient in TcdA (A-B+) or TcdB (A+B-), and the wild type, we investigated how and why treatment of infected animals with anti-TcdA dramatically increased disease severity. Contrary to the hypothesis, among piglets treated with anti-TcdA, those with A+B- infection were disease free, in contrast to the disease enhancement seen in those with wild-type or A-B+ infection. It seems that the lack of TcdA, through either 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.