| Other Clostridioides difficile Indications

Alexander Khoruts, MD

Given the evidence of FMT for recurrent Clostridium difficile infection (rCDI; previously recurrent Clostridium difficile infection),¹ there has been interest in the use of FMT for primary CDI. It appears to be the most effective treatment for prevention of recurrent infection, so it stands to reason that it should be similarly effective for treatment of primary infection or prevention of a first recurrence. In many cases, diarrhea caused by C. difficile is characterized by debilitating symptoms that include extreme fecal urgency and episodes of fecal incontinence, abdominal cramps, high frequency of bowel movements during the day and night, and exhaustion. Patients often become terrified that the infection may return, knowing that there is a 20% to 30% chance of recurrence following initial treatment of CDI.² Several perspectives need to be considered in answering this question: scientific, financial, and legal. This section outlines the role of FMT for primary CDI.

It is important to emphasize that at this time, FMT is generally offered following antibiotic treatment, typically vancomycin, and used to prevent further CDI recurrence. It is assumed that success of FMT is at least partially dependent on prior antibiotic-mediated suppression of vegetative C. difficile bacteria-producing toxins, while FMT restores the intestinal microbial community structure and microbiota-mediated colonization resistance to C. difficile.3 Recently, a small proof-of-concept trial compared metronidazole treatment with FMT delivered via enema (60 mL, anaerobically prepared) for the treatment of primary CDI (Figure 10.1.1-1).⁴ The primary outcome was clinical cure, defined as < 3 bowel movements per day and no evidence of recurrence at day 70. Overall, 5 of 9 patients responded to treatment in the FMT arm, which was comparable to 5 of 11 responders in the metronidazole group. By day 4 after treatment, the remaining 4 FMT patients were given metronidazole, only 2 of whom had adequate secondary response. From a safety perspective, there were no safety events in either arm. There were some limitations with this study, beyond the small sample size. Specifically, the investigators compared metronidazole with FMT administered by enema. Notably, metronidazole is no longer recommended for primary therapy of CDI in adults because of lesser efficacy and greater side effects compared with other antibiotics.³ In addition, administration of FMT by enema may be less efficacious relative to other routes, such as colonoscopy or capsule.⁵ The investigators are now conducting a Phase 3 trial to evaluate FMT as a primary treatment of CDI.

Importantly, fulminant CDI, which commonly presents as primary infection, must be regarded as a distinct clinical entity. It is a disease characterized by high mortality and morbidity and needs to be treated in the most urgent manner. FMT is an important consideration in management of this CDI presentation, and this topic is covered in much greater detail in Chapter 10.1.2: “The Role of Fecal Microbiota Transplantation in the Treatment of Severe and Fulminant Clostridioides difficile Infection.” Briefly, in our unique University of Minnesota experience, in a series of 16 patients (unpublished), some of the most common factors that are associated with poor outcomes in fulminant CDI management include late recognition of disease severity and delayed specialist consultation, concurrent use of broad-spectrum antibiotics for sepsis (typically without another source), and use of narcotics for pain control. In our center, we offer FMT after failure to document clinical benefit following at least 48 hours of appropriate medical therapy. In most cases, FMT leads to prompt improvement within 24 to 48 hours of FMT by colonoscopy, which is documented by clinical signs and symptoms, hemodynamic parameters, and inflammatory markers. Importantly, FMT in treatment of fulminant CDI generally needs to be administered more than once because of high risk of recurrence following a single treatment.^6,7 Our current FMT protocol for fulminant CDI includes (1) specialist consensus (gastroenterology, infectious disease, and colorectal surgery); (2) discontinuation of all antibiotics; followed by (3) FMT by colonoscopy as initial treatment; (4) resumption of antibiotics against CDI (vancomycin or fidaxomicin) 3 days after the initial FMT (patients are typically discharged from the hospital shortly after); and finally (5) a consolidation treatment with FMT by capsules given on an outpatient basis. The initial colonoscopic delivery of FMT is important for documentation of pseudomembranous colitis, because it is not uncommon to see fulminant CDI-like clinical presentation where the septic picture is driven by another source. The goal of this initial treatment is clinical stabilization. Once the patient is discharged, the syndrome can be considered equivalent to outpatient rCDI, where the remaining treatment goal is prevention of CDI recurrence. Logistically, oral capsules provide the easiest formulation for most such patients.