Iron Effects on Clostridioides difficile Toxin Production and Antimicrobial Susceptibilities

Despite the benefits of red blood cell (RBC) transfusion therapy, it can render patients vulnerable to iron overload. The excess iron deposits in various body tissues cause severe complications and organ damage such as cardiotoxicity and mold infections. Clostridioides difficile infection (CDI) is the most common cause of nosocomial diarrhea among cancer patients and is associated with significant morbidity and mortality. Our study aims to determine the role of iron overload and the effects of iron chelators on CDI. Our results demonstrated that iron (Fe(3+)) stimulated the growth of C. difficile with increased colony formation units (CFU) in a dose-dependent manner. Exposure to excess iron also increased the gene expression levels of tcdA and tcdB. The production of C. difficile toxin A, necessary for the pathogenesis of C. difficile, was also elevated after iron treatment. In the presence of excess iron, C. difficile becomes less susceptible to metronidazole with significantly elevated minimum inhibitory concentration (MIC) but remains susceptible to vancomycin. Iron-stimulated colony formation and production of C. difficile toxins were effectively diminished by iron chelator deferoxamine co-treatment. Incorporating iron overload status as a potential factor in developing a risk prediction model of CDI and antibiotic treatment response may aid clinical practitioners in optimizing CDI management in oncology patients.