Preventing Recurrent CDI: New, Old, and Really Old Strategies

Rossana M. Rosa, MD


June 15, 2017

Editorial Collaboration

Medscape &

Preventing Clostridium difficile Recurrence

Three recent studies tackled strategies aimed at preventing recurrent Clostridium difficile infection (RCDI).

Adding a single dose of bezlotoxumab—a monoclonal antibody that neutralized C difficile toxin B—to standard therapy significantly reduced the rate of RCDI compared with antibiotics alone. The results come from two industry-funded phase 3 trials,[1] in which 2655 adult patients receiving standard therapy (vancomycin, metronidazole, or fidaxomicin) were randomly assigned to four treatment groups: bezlotoxumab alone, bezlotoxumab plus actoxumab, actoxumab alone, or placebo. The primary endpoint was the proportion of patients with RCDI (defined as a new episode of C difficile infection during the 12 weeks of follow-up after initial cure).

In the first trial, the proportion of patients who experienced RCDI in the bezlotoxumab group was significantly lower compared with the placebo group (17% vs 28%).

In the second trial, RCDI occurred in 16% of the bezlotoxumab group compared with 26% of the placebo group. The use of actoxumab alone or in combination did not significantly affect recurrence rates. In the pooled analysis, the rates of sustained cure were 64% with bezlotoxumab alone, 58% with bezlotoxumab plus actoxumab, and 54% with placebo.

A large retrospective study[2] found that rates of RCDI were similar among patients treated with vancomycin or metronidazole. Treatment with vancomycin was associated with a reduction in the 30-day mortality risk, mainly among patients with severe C difficile infection.

Researchers at the Veterans Administration Healthcare System reviewed records of patients treated at their facilities between 2005 and 2012, and built a propensity-matched cohort (based on the probability of receiving vancomycin). The primary outcomes of interest were RCDI and all-cause 30-day mortality. Recurrence was defined as a positive laboratory test for C difficile anytime between days 14 and 56 after initial diagnosis. Three separate propensity-matched cohorts were generated, on the basis of disease severity (any severity [n = 10,137], mild to moderate [n = 5452], and severe [n = 3130]).

Rates of recurrence did not statistically significantly differ among severity groups regardless of treatment. In the any severity cohort, 30-day mortality risk was lower for patients treated with vancomycin than for those treated with metronidazole (8.6% vs 10.6%; P = .01). Larger differences were seen in the severe C difficile infection cohort, where the 30-day mortality risk was 15.3% for patients treated with vancomycin versus 19.8% for those treated with metronidazole (P = .01). No difference in mortality risk was seen among patients with mild disease.

Finally, how can we prevent RCDI in patients with urinary tract infection (UTI)? A 3-day course of parenteral aminoglycoside was found to be safe and effective in the treatment of uncomplicated UTI in patients at high risk for RCDI.[3] Researchers enrolled 20 consecutive patients who had received a fecal microbiota transplantation (FMT) for the management of RCDI, and who were subsequently diagnosed with an uncomplicated UTI. The protocol consisted of gentamicin 160 mg (intramuscular or intravenous) on day 1, and 80 mg on days 2 and 3, administered in an outpatient setting.

All patients had prompt resolution of UTI symptoms, and none had RCDI. The only adverse event reported was pain at the injection site in one patient. In three patients, fecal bacterial composition was analyzed before and after therapy with gentamicin, and no substantial shifts were found.


After an initial episode of C difficile infection, recurrence of disease can affect up to 50% of patients[4]—hence the interest in tackling this issue from different angles. The study by Stevens and colleagues[2] found that our current go-to drugs—vancomycin and metronidazole—are associated with similar recurrence rates; however, oral vancomycin should be the drug of choice for patients with severe disease.

The use of bezlotoxumab led to a modest reduction of C difficile recurrence, but its high cost is another consideration.

The study by Staley and colleagues[3] highlights the challenges in preserving the gut microbiome of patients who have undergone FMT for treatment of RCDI. A short course of parenteral aminoglycosides safely and effectively treated UTIs among this patient population, with minimal disruption of their fecal bacterial composition. However, this was a small study, so the results should be interpreted with caution.

Clinical practice pearls:

  • Oral vancomycin should the treatment of choice for patients with severe C difficile infection.

  • A single dose of bezlotoxumab reduced RCDI rates at 12 weeks—but cost may be an issue.

  • In patients who received FMT for the treatment of RCDI, a 3-day course of parenteral aminoglycosides appears to be a safe and effective therapeutic option for the treatment of uncomplicated UTIs while preserving the fecal bacterial composition.


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