Dear Colleagues,

Forty years ago, Clostridioides difficile was identified as the cause of pseudomembranous colitis and of many cases of antibiotic-associated diarrhea, and it is now recognized as the leading single hospital-acquired infection in the United States and likely worldwide. In the last 15–20 years, there has been a surge in case-rates, complications and scientific inquiries related to C. difficile. These have translated into important changes in diagnostic and therapeutic paradigms, which are discussed in this Special Issue. 

The preferred diagnosis of C. difficile has evolved over time—from assays detecting the pathogenic C. difficile toxin proteins (e.g., cytotoxicity assays and immunoassays), to assays detecting the DNA of toxigenic strains via nucleic acid amplification (e.g., PCR), and now, we have reverted back to toxin detection. While DNA assays are most sensitive, there is increasing recognition that toxin assays correlate best with severe disease and the need for treatment. At the same time, newer, more sensitive toxin assays have sensitivity levels similar to the sensitivity of PCR; the clinical impact of these newer assays needs to be determined. Finally, C. difficile culture has been considered impractical for clinical use but remains invaluable in strain typing and epidemiologic studies. 

The approach to the treatment of C. difficile has also evolved in the past decade, with a new emphasis on 1. the goal of a sustained clinical response—i.e., clinical improvement without the recurrence of diarrhea; and 2. the role of “normal” intestinal microbiota (“good flora”) in preventing infection and relapse through C. difficile. These considerations highlight the challenges of treating C. difficile, whereby relapse typically occurs in 20% of patients, with repeated recurrences in 5–10% of patients. Thus, the most selective antimicrobials—active against C. difficile but sparing normal flora—have demonstrated the greatest sustained clinical response. Furthermore, antibodies against C. difficile toxins facilitate the clearance of the organism and decrease relapse. Finally, the restoration of “good microflora” via fecal microbiota transplant (FMT) has demonstrated unprecedented outcomes in the difficult-to-treat population of frequent relapsers. While colonoscopies were originally required to introduce “good” fecal microbiota, newer modalities such as fecal capsules are making this FMT methodology more acceptable, more available and increasingly considered in scenarios such as severe disease or even instances of first relapse. Caveats to this methodology include the inconsistency and uncertainty of active components, potential for the transmission of infectious agents and costs. 

Two unique scenarios present special therapeutic challenges. First, colonization by C. difficile without diarrheal disease may be protective against subsequent disease, or it may be a precursor for clinical disease. The potential role of prophylactic treatment in this population is debated, while infection control measures seem to be effective. At the other extreme, we lack clear evidence-based interventions for severe C. difficile disease, although some antibiotic, FMT and surgical approaches seem to be effective.

Dr. Paul F. Riska
Guest Editor

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• Clostridioides difficile
• diagnosis
• treatment
• antibiotic-associated diarrhea
• fecal microbiota transplant