The impact of Actotoxumab treatment of gnotobiotic piglets infected with different Clostridium difficile isogenic mutants.J Infect Dis 2019JI
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.