Treatment of Recurrent C. difficile Infection

Initial Management

The American Gastroenterological Association recommends fecal microbiota-based therapy for immunocompetent adults with recurrent C. difficile infection upon completion of standard antibiotic treatment, achieving 87-92% clinical resolution compared to 40-50% with antibiotics alone 1, 2

For patients with recurrent C. difficile infection, a vancomycin tapered and pulsed regimen can be used if fecal microbiota-based therapy is not immediately available, with a regimen of vancomycin 125 mg every 6 hours for 10-14 days, then 125 mg every 12 hours for 7 days, then 125 mg every 24 hours for 7 days, and finally 125 mg every 48-72 hours for 2-8 weeks 2, 3
The British guidelines support offering fecal microbiota-based therapy after at least two recurrences, or after one recurrence in patients with risk factors for further episodes 4
Fecal microbiota-based therapy demonstrates 81-92% sustained resolution rates across multiple studies, significantly superior to antibiotic therapy alone 2, 3

The American Gastroenterological Association recommends considering fecal microbiota-based therapy after the second recurrence (third episode) or earlier in select high-risk patients who have recovered from severe/fulminant C. difficile infection or have significant comorbidities 1
Fecal microbiota-based therapy can be delivered via colonoscopy, nasojejunal tube, or FDA-approved oral formulations with similar efficacy 1, 4

Discontinue proton pump inhibitors if not absolutely required, as they are associated with increased C. difficile recurrence risk 3, 5
Avoid high-risk antibiotics including clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones 3
Never use antimotility agents (loperamide, opiates) as they can worsen outcomes and precipitate toxic megacolon 5

Watch for warning signs requiring escalation, including WBC ≥25,000 or rising, lactate ≥5 mmol/L, ileus or toxic megacolon, peritoneal signs, and serum creatinine >1.5 mg/dL or rising 3, 5, 6

Do not test for cure, as testing asymptomatic patients after treatment is not recommended, and PCR can remain positive for weeks despite clinical resolution 1
Recurrent diarrhea after C. difficile treatment may represent alternative diagnoses rather than true C. difficile recurrence, especially if symptoms are atypical or unresponsive to vancomycin 1

For the first recurrence, fidaxomicin (standard or extended-pulsed regimen) is preferred over vancomycin, demonstrating superior sustained clinical response at 30 days (RR: 1.27; 95% CI: 1.05–1.54) with significantly lower subsequent recurrence rates (19.7% vs 35.5%, P = .045) in patients with recurrent C. difficile infection, according to the Infectious Diseases Society of America 7, 8
A standard 10-14 day course of vancomycin 125 mg four times daily is an alternative acceptable option for first recurrence, particularly if metronidazole was used initially, with a clinical response rate of 80-90% in patients with mild to moderate C. difficile infection 9

Fidaxomicin extended-pulsed regimen is an alternative option for multiple recurrences, with a sustained clinical response rate of 70-80% in patients with recurrent C. difficile infection 7, 8
Vancomycin standard course followed by rifaximin 400 mg three times daily for 20 days is another alternative option for multiple recurrences, with a clinical response rate of 60-70% in patients with recurrent C. difficile infection 9

The use of bezlotoxumab is not recommended as an adjunctive therapy for patients with recurrent C. difficile infection, as it is not an antibacterial drug and does not treat CDI, but rather reduces recurrence risk, according to the American Gastroenterological Association 7, 8
However, the American College of Gastroenterology does not have a recommendation for bezlotoxumab, but the Infectious Diseases Society of America recommends considering adding bezlotoxumab 10 mg/kg as a single IV infusion during or shortly after completion of antibiotic therapy for patients at high risk of recurrence, such as those with a history of CDI in the past 6 months or immunocompromised state 7, 8

The American Gastroenterological Association recommends verifying clinical criteria, including ≥3 unformed stools in 24 hours with a positive C. difficile test, to diagnose recurrent CDI 10
The Infectious Diseases Society of America suggests ruling out alternative causes, such as post-infectious irritable bowel syndrome, inflammatory bowel disease flare, medication side effects, or other infections, especially if symptoms include diarrhea alternating with constipation or lack of response to vancomycin/fidaxomicin 10
Fecal microbiota transplantation (FMT) is the treatment of choice for confirmed recurrent CDI after fidaxomicin failure, achieving 87-92% clinical resolution compared to 40-50% with additional antibiotic courses 10
The American College of Gastroenterology recommends administering FMT upon completion of a standard course of CDI antibiotics, with bridging therapy using suppressive vancomycin until FMT is administered 10
Bezlotoxumab 10 mg/kg as a single IV infusion during or shortly after antibiotic completion may be considered for patients at high risk of further recurrence, including those with a history of CDI in the past 6 months, immunocompromised state, age ≥65 years, or severe CDI 11

FMT appears safe for mildly to moderately immunocompromised patients, but should be avoided in severely immunocompromised patients, such as those on active cytotoxic therapy or recent stem cell transplant 10
Patients requiring frequent antibiotics should be considered for alternative treatments, such as extended vancomycin taper, as ongoing antibiotics may diminish FMT efficacy 10

Discontinuing non-essential antibiotics immediately and stopping proton pump inhibitors unless absolutely required can help reduce CDI recurrence risk 10
Avoiding high-risk antibiotics, such as clindamycin, third-generation cephalosporins, fluoroquinolones, and broad-spectrum penicillins, can also help reduce recurrence risk 10