Clostridium difficile infection (CDI) represents the most prevalent cause of 
antibiotic-associated gastrointestinal infections in health care facilities in 
the developed world. Disease symptoms are caused by the two homologous 
exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of 
antibiotics that are associated with a high rate of disease recurrence, 
highlighting the need for novel treatment paradigms that target the toxins 
rather than the organism itself. A combination of human monoclonal antibodies, 
actoxumab and bezlotoxumab, directed against TcdA and TcdB, respectively, has 
been shown to decrease the rate of recurrence in patients treated with 
standard-of-care antibiotics. However, the exact mechanism of antibody-mediated 
protection is poorly understood. In this study, we show that the antitoxin 
antibodies are protective in multiple murine models of CDI, including systemic 
and local (gut) toxin challenge models, as well as primary and recurrent models 
of infection in mice. Systemically administered actoxumab-bezlotoxumab prevents 
both the damage to the gut wall and the inflammatory response, which are 
associated with C. difficile in these models, including in mice challenged with 
a strain of the hypervirulent ribotype 027. Furthermore, mutant antibodies 
(N297Q) that do not bind to Fcγ receptors provide a level of protection similar 
to that of wild-type antibodies, demonstrating that the mechanism of protection 
is through direct neutralization of the toxins and does not involve host 
effector functions. These data provide a mechanistic basis for the prevention of 
recurrent disease observed in CDI patients in clinical trials.