Randomised Clinical Trial

Faecal Microbiota Transplantation by Colonoscopy Plus Vancomycin for the Treatment of Severe Refractory Clostridium Difficile Infection

Single Versus Multiple Infusions

G. Ianiro; L. Masucci; G. Quaranta; C. Simonelli; L. R. Lopetuso; M. Sanguinetti; A. Gasbarrini; G. Cammarota


Aliment Pharmacol Ther. 2018;48(2):152-159. 

In This Article

Abstract and Introduction


Background: Faecal microbiota transplantation (FMT) is a highly effective treatment against recurrent Clostridium difficile infection. Far less evidence exists on the efficacy of FMT in treating severe Clostridium difficile infection refractory to antibiotics.

Aim: To compare the efficacy of two FMT–based protocols associated with vancomycin in curing subjects with severe Clostridium difficile infection refractory to antibiotics.

Methods: Subjects with severe Clostridium difficile infection refractory to antibiotics were randomly assigned to one of the two following treatment arms: (1) FMT–S, including a single faecal infusion via colonoscopy followed by a 14–day vancomycin course, (2) FMT–M, including multiple faecal infusions plus a 14–day vancomycin course. In the FMT–M group, all subjects received at least two infusions, while those with pseudomembranous colitis underwent further infusions until the disappearance of pseudomembranes. The primary outcome was the cure of refractory severe Clostridium difficile infection.

Results: Fifty six subjects, 28 in each treatment arm, were enrolled. Twenty one patients in the FMT–S group and 28 patients in the FMT–M group were cured (75% vs 100%, respectively, both in per protocol and intention–to–treat analyses; P = 0.01). No serious adverse events associated with any of the two treatment protocols were observed.

Conclusions: A pseudomembrane–driven FMT protocol consisting of multiple faecal infusions and concomitant vancomycin was significantly more effective than a single faecal transplant followed by vancomycin in curing severe Clostridium difficile infection refractory to antibiotics. Clinical-Trials.gov registration number: NCT03427229.


Clostridium difficile (now called Clostridioides difficile) infection (CDI) is the most common hospital–acquired cause of diarrhoea, and has become a major challenge for healthcare systems, accounting for nearly $5 billion in healthcare cost[1,2] and 29 000 deaths[3] per year in the United States. The burden of CDI in the last decade can be explained mostly by the increase in incidence, severity, mortality, and likelihood of recurrence.[3] Most recent data show that nearly 20% of patients with newly diagnosed CDI recur after standard antibiotic therapy, and recurrence rates rise up to 50%–60% after the second recurrence.[4,5]

Due to its resistance to antibiotics, recurrent CDI is more likely to present with a severe clinical picture, which increases the risk of life–threatening complications (ie toxic megacolon, sepsis) and death.[6]

Faecal microbiota transplantation (FMT) is a highly effective and durable therapy for recurrent CDI,[7–10] and it is recommended as the best therapeutic option for recurrent disease after failure of antibiotics.[11–14] Evidence suggests that FMT may be a promising treatment also for severe CDI refractory to antibiotics, as reported cure rates range from 50% to 91%.[15–21] Due to high morbidity and mortality associated with colectomy,[22] the use of FMT has been recommended in this subset of patients,[13] although there is still considerable uncertainty about the best therapeutic protocol to adopt.

As reported in most studies, single–infusion FMT is likely to provide only transient improvement in patients with severe CDI and pseudomembranous colitis, and multiple infusions are often necessary to obtain sustained cure.[17–20] In our early experience, we administered repeated faecal infusions to patients with pseudomembranous colitis until the disappearance of pseudomembranes, achieving a 100% cure rate in patients treated with this approach.[8] More recently, Fischer and colleagues described a specific protocol for severe and complicated CDI including an initial faecal infusion in all patients, further vancomycin treatment in those with pseudomembranes, and repeated FMT in nonresponders.[18,20] In their largest report, the authors achieved nearly 53% and 96% efficacy rates with single and repeated faecal infusions, respectively.[20] In two other cohort studies,[17,23] multivariate analysis found severe CDI to be an independent predictor of failure after single faecal infusion.

Although preliminary data is promising, the definition of an effective FMT protocol for severe CDI is limited by the absence of randomised trials comparing single versus multiple infusions. Accordingly, we aimed to compare the efficacy of two different FMT protocols including, respectively, single or multiple faecal infusions plus vancomycin for the treatment of severe CDI refractory to antibiotics.