Abbas Rupawala, MD and Colleen R. Kelly, MD
Clostridioides difficile (previously Clostridium difficile) is an anaerobic gram-positive bacillus that has emerged as the most common cause of hospital-acquired infection in the past 2 decades. The incidence of recurrent C. difficile infection (rCDI) has nearly doubled since 2001, and multiply-recurrent infection has increased nearly 200% over the same period of time.1 Factors including the increased use of antibiotics and their effect on gut microbiota and the emergence of more virulent strains have contributed to the higher occurrence of both health care–associated and community-acquired C. difficile infection (CDI) as well as more severe and fulminant cases. Although an altered gut microbiome is central to the pathophysiology of CDI, the standard treatment for primary and recurrent episodes remains antibiotics, often given as long, tapering courses, which control the infection but do little to restore the microbiome to a healthy, diverse state.
A number of small randomized clinical trials have reported high efficacy rates for fecal microbiota transplantation (FMT) following standard-of-care (SOC) antibiotics to prevent rCDI,2 and FMT is increasingly being used in acute severe and fulminant disease.3,4 In this chapter, we will review the relevant data supporting FMT for treatment of CDI as well as the clinical evaluation, diagnostic dilemmas, and decision making around administering FMT.
Recurrent Clostridioides difficile Infection
The efficacy of FMT following SOC antibiotics for preventing rCDI has been well described in numerous case series and randomized clinical trials, with clinical cure rates reported from 68% to 100%. The first randomized clinical trial evaluating the efficacy of FMT in rCDI, in which FMT was administered by nasoduodenal infusion and showed statistically superior cure rates (81% for single administration) compared with vancomycin (31%), and the trial was stopped early by the institutional research board for benefit, was published in 2013.5 Subsequently, other small randomized clinical trials in rCDI have largely replicated these results when comparing FMT following SOC antibiotics to other interventions, including autologous stool transplant as placebo,6 vancomycin alone,7 and fidaxomicin alone.8 Efficacy has been reported as similar with fresh, frozen,9 and lyophilized material,10 and high success rates have been observed regardless of mode of FMT administration, including oral capsules (Table 4-1).11
Most investigators have defined rCDI as 3 or more episodes, although a number of trials have performed FMT after 2 episodes. Overall, the number needed to treat for FMT is 3 (95% confidence interval, 2-7) to prevent CDI recurrence following SOC antibiotics.2 Although there is variation and a lack of consensus on the definition of rCDI, all CDI clinical practice guidelines recommend FMT for individuals who have suffered more than 3 CDI episodes (2 or more recurrences).12–14
Although CDI diagnosis may be obvious, such as in a patient presenting with profuse watery diarrhea and leukocytosis who responds clinically to oral vancomycin, some patients present with atypical symptoms, and relying heavily on results of polymerase chain reaction (PCR)–based stool testing may result in diagnostic errors. Studies from high-volume tertiary centers have reported alternative, non-CDI diagnoses in as many as 25% of patients referred for rCDI.15,16 Highly sensitive molecular testing detects the presence of the toxin gene (may or may not be on), and if PCR-based stool tests are used in isolation, they may lead to a high false-positive rate for the diagnosis of CDI. In contrast to toxin enzyme immunoassays (toxin EIA) test directly for the presence of toxins and have a high specificity. Clinical guidelines recommend a 2-step algorithm with a highly sensitive test (PCR or glutamate dehydrogenase [GDH]) followed by a highly specific test (toxin EIA).
Rates of asymptomatic C. difficile colonization with a toxigenic strain are as high as 15% in heathy adults and may reach 50% in residents of long-term care facilities.17 Patients who are colonized and have a non-CDI etiology of diarrheal symptoms may be incorrectly classified as CDI if only the results of a PCR assay are considered. Furthermore, post-infection irritable bowel syndrome (IBS) is common after CDI,18 and these colonized patients with ongoing diarrheal symptoms may be treated unnecessarily with repeated courses of vancomycin or FMT (Figure 4-1).
Obtaining a detailed history around the CDI is important (Practical Pearls 4-1 and 4-2). Patients who are inappropriately tested for cure after resolution of diarrheal symptoms and found to be stool PCR positive should not be treated or considered for FMT. Atypical features, such as intermittent, nonprogressive symptoms and nonresponse to SOC antibiotics (eg, vancomycin), should raise concern that a patient’s symptoms are not due to CDI. Patients who describe long duration of symptoms (months) prior to initial diagnosis are unlikely to be experiencing CDI as the source of those symptoms. In terms of laboratory investigations, because PCR-positive, toxin EIA–negative patients do not appear to experience complications or require treatment,19 it is recommended to conduct a 2-step C. difficile testing algorithm instead of using a PCR-based stool test alone. Fecal calprotectin, a marker of gastrointestinal (GI) inflammation, is typically elevated in CDI and may also be helpful in distinguishing colonization from active infection. Specifically, a fecal calprotectin that is low or normal may suggest colonization as compared with a CDI episode.20 In patients where the diagnosis of CDI is uncertain, workup may also include celiac serologies, Giardia testing, fecal fat stain, and colonoscopy with mucosal biopsies to exclude inflammatory bowel disease (IBD) and microscopic colitis. This workup is particularly important in younger patients (< 65 years) who are at highest risk for an alternative diagnosis mimicking rCDI.15,16