In this study, we examined the applicability of the ADAPT platform to sdAb affinity maturation while continuing our efforts towards improved therapies for Clostridium difficile infections (CDI). Treatment of CDI with antibiotics can result in recurrent forms of this highly common and costly hospital-acquired disease. With the emergence of antibiotic-resistant and hypervirulent C. difficile strains, CDI-associated health-care costs and morbidity rates have prompted alternative treatment modalities including vaccines, fecal transplantation, probiotics and antibody-based immunotherapy. With regard to antibody-based immunotherapy, a number of mAbs targeting and neutralizing C. difficile virulence-factor toxins A and B (TcdA and TcdB) have been discovered, with the anti-TcdB mAb bezlotoxumab recently passing a Phase III clinical trial and obtaining FDA-approval. SdAbs are also attractive immunotherapeutics, as they present several advantages over mAbs, primarily in terms of ability to access cryptic and concave epitopes, increased stabilities, high modularity and smaller size, thus potentially leading to excellent efficacy, pharmacokinetics and developability profiles.