JAMA Insights
Recurrent Clostridioides difficile Infections
Joffrey van Prehn, Ed J. Kuijper, Erik R. Dubberke
JAMA Published Online: October 20, 2025
doi: 10.1001/jama.2025.18089
Clostridioides difficile is a gram-positive spore-forming anaerobic bacterium that can produce toxins. After ingestion of C difficile spores, which can be found in health care institutions and homes of healthy people, the intestines can become colonized. In healthy individuals, gut bacteria, bile-acid metabolism, and the immune system can suppress spore germination. However, changes to the gut bacteria (eg, from antibiotics) can lead to C difficile overgrowth and toxin production, converting asymptomatic colonization into symptomatic infection. Toxins A/B bind to colonic epithelium receptors causing inflammation and cell death, leading to diarrhea and colitis. Fecal toxin levels correlate with increased disease severity, recurrence, and mortality.1 Symptoms of C difficileinfection (CDI) range from mild infection (60%-80%) with diarrhea to fulminant colitis requiring intensive care unit admission (approximately 6% of reported cases per US Centers for Disease Control and Prevention [CDC] 2022 surveillance), colectomy, and death (approximately 2%).
Recurrent CDI (rCDI) is defined as recurrence of diarrhea (≥3 unformed stools within 24 hours) within 8 weeks of symptom resolution and completion of treatment for a previous CDI episode. rCDI differs clinically from refractory CDI, which is rare and involves lack of response to initial treatment, usually occurring with fulminant infection (eg, septic shock, toxic megacolon, bowel perforation). CDI can recur because, despite treatment, spores can persist in the colon and may germinate and produce toxins if the microbiota is further disrupted (eg, with additional antibiotics). However, up to 50% of rCDI is caused by ingestion of spores from a new toxin-producing strain.
Epidemiology
Surveillance data from the CDC in 2022 reported a CDI incidence of 116.1 per 100 000 persons, with rates of community-associated CDI higher than health care-associated CDI (62.1 per 100 000 vs 54.0 per 100 000). In 2017, the CDC estimated there were 69 800 first recurrences of CDI in the US.2 Approximately 70% of recurrences occur within 4 weeks after treatment; rCDI incidence increases to 40% to 50% after a first recurrence.
Risk Factors
Antibiotic use is the primary risk factor for CDI. Clindamycin, fluoroquinolones, cephalosporins, and carbapenems may be associated with the highest risk of CDI.3-6 A systematic review that included 43 mostly retrospective studies reported that rCDI was associated with older age (≥65 years), prior rCDI, health care–associated CDI, and proton-pump inhibitor use. Other rCDI risk factors include strains associated with poor outcomes (ribotypes 027/078/244), compromised immunity, and severe CDI.
Diagnosis
Diagnostic tests for CDI include toxin enzyme immunoassays (EIAs), which detect free toxins; nucleic acid amplification tests (NAATs), which detect presence of C difficile toxin genes; and glutamate dehydrogenase, an enzyme produced by all C difficile strains, even those that do not produce toxins. NAATs have higher sensitivity for diagnosing CDI than toxin EIAs (96% [95% CI, 93%-98%] vs 83% [95% CI, 76%-88%]), but are less specific (94% [95% CI, 93%-95%] vs 99% [95% CI, 98%-99%]). A negative NAAT result rules out CDI, but a positive NAAT result does not distinguish between asymptomatic colonization and CDI. For CDI diagnosis, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends combining a sensitive screening assay (glutamate dehydrogenase testing or NAAT) with highly specific test (toxin EIA), only testing unformed stool, and avoiding retesting patients with recent CDI without recurrent symptoms.
Distinguishing active infection from colonization is challenging in rCDI because colonization may persist after successful treatment (>50% culture of a toxigenic strain after 1 week).7 Postinfectious irritable bowel syndrome–like symptoms (irregular defecation patterns) after CDI occurred in 21.1% (95% CI, 8.2%-35.7%) of patients in a meta-analysis (N = 1218 patients) of 15 cohort studies of post-CDI symptoms, and may persist up to 2 years after CDI. Positive diagnostic test results (NAAT or EIA), presence of symptoms (diarrhea, fever, abdominal pain), absence of other causes of diarrhea, and previous CDI response to antibiotic treatment help establish rCDI diagnosis (Figure). Alternative diagnoses should be considered for patients with CDI who do not improve with treatment because resistance to anti-CDI antibiotics is rare: less than 2% metronidazole resistance and no vancomycin and fidaxomicin resistance was found in a 2018 European surveillance study.
Figure. Diagnosis of Recurrent Clostridioides difficile Infection
Treatment
As first-line treatment for initial CDI, the IDSA/SHEA and ESCMID recommend fidaxomicin oral, 200 mg, twice daily for 10 days, which is associated with decreased recurrences compared with oral vancomycin (125 mg 4 times daily for 10 days) at 4 weeks (cure without recurrence: 71% vs 61%; risk ratio, 1.17 [95% CI, 1.04-1.31]). For the first episode of rCDI, fidaxomicin is also recommended by IDSA/SHEA and ESCMID; alternative options include extended fidaxomicin (200 mg twice per day on days 1-5, then once daily on alternate days on days 7-25) or oral vancomycin taper (eg, 125 mg 4 times daily for 10 to 14 days, 2 times daily for 7 days, once daily for 7 days, and then every 2 to 3 days for 2 to 8 weeks).
For adults with a second or subsequent CDI recurrence after first-line antibiotic treatment, IDSA/SHEA, American Gastroenterologist Association (AGA), and ESCMID recommend fecal microbiota transplant (FMT). Approximately one-quarter of patients undergoing FMT have mostly mild and self-limiting adverse events such as diarrhea and abdominal discomfort/bloating/cramping; long-term consequences of FMT are unclear. A systematic review of FMT adverse effects (129 studies; 4241 patients) reported 1.4% of patients had serious adverse events, including 1 probably and 4 definitely FMT-related deaths (1 aspiration during sedation, 1 aspiration of FMT, 1 regurgitation of FMT, 1 post-FMT pneumonia with sepsis). The American Gastroenterologist Association suggests against FMTin severely immunocompromised individuals, such as those receiving cytotoxic treatment for malignancies and advanced HIV (CD4 cell count <c200) due to potential risk of transmitting infections via FMT.
Conventional FMT is produced by donor stool banks and involves administration of suspensions or capsules with feces from screened donors via the oral, duodenal, or colonic route, with the goal of restoring a healthy gut microbiota. Commercial US Food and Drug Administration–approved fecal microbiota products for rCDI include processed donor stool and donor-derived fecal bacterial spores. Pooled efficacy of 1 dose of FMT or fecal microbiota products to prevent CDI recurrences in 10 randomized trials including 523 patients with rCDI was 72% (95% CI, 60%-82%), with follow-up ranging from 8 to 24 weeks. In comparison, efficacy of oral vancomycin for multiple rCDI is about 30%.8 A microbiota product made from clonal bacterial cell banks is being tested in phase 3 trial.
Secondary antibiotic prophylaxis after CDI (eg, vancomycin, fidaxomicin) might reduce CDI incidence, but is discouraged because of a lack of conclusive evidence and concerns about microbiota selection and antimicrobial resistance, but may be considered in frail or immunosuppressed patients with multiple previous CDI episodes or patients with prior severe CDI episodes. Probiotics for primary and secondary prevention of CDI in high-risk populations might be beneficial, but are not guideline recommended because studies use different probiotics formulations (eg, Lactobacillus, Bifidobacterium, or Saccharomyces species) and report conflicting results.9,10
Conclusions
CDI recurrence affects about 14% to 16% of patients with CDI, and the risk of recurrence increases with each CDI episode. Fecal microbiota transplant is recommended for adults with 2 or more CDI recurrences after first-line antibiotic treatment.
