Fecal Transplant vs Vancomycin for Recurrent C Difficile
Fecal Transplant vs Vancomycin for Recurrent C Difficile
From July 2013 through June 2014, 39 patients (F = 23, M = 16, mean age 73 years) were randomly assigned to one of the following treatments: FMT (20 subjects, F = 12, M = 8, mean age: 71 years) or vancomycin regimen (19 subjects, F = 11, M = 8, mean age 75 years). No patient refused the proposed treatment. At the planned 1-year interim analysis, FMT showed a significantly higher efficacy than vancomycin. Therefore, after consulting an independent committee (including two internists and one gastroenterologist), the study was stopped when a total of 39 patients were recruited.
In 23 of the 39 (59%) patients, a positive toxin test before inclusion was confirmed by a positive C. difficile culture. All enrolled patients completed the study protocol.
Baseline demographic and clinical characteristics of the patients are provided in Table 1.
Most approved donors were relatives of the patients (16 subjects); in two cases, the donors were intimates and in another two FMT cases, the donor was unrelated because the patients had no relatives. The unrelated donor was a subject that had previously served as a donor for his relative. Therefore, faeces from a total of 18 donors were used to treat 20 subjects in the infusion group. A mean (±s.d.) of 152 ± 32 g of faeces was infused. The mean time from defecation to infusion was 3.8 ± 0.8 h.
The first two patients in the FMT group had PMC. One of these two subjects had a recurrence after 1 week after an initial resolution of symptoms and thus underwent another faecal infusion. Although with the second procedure, we noted a partial reduction in the presence of pseudo-membranes and initial symptom resolution, the patient had another recurrence after 5 days. Therefore, the patient was treated with vancomycin but died from sepsis after 1 week. The second patient with PMC was affected by severe cardiopathy; he was initially treated with a faecal infusion. After an apparent initial amelioration of diarrhoea with an objective reduction in the thickening of the colonic wall during the TC examination, the patient had a recurrence 5 days after the faecal infusion procedure. Due to the deterioration of the general clinical condition of this patient, we could not offer him a second infusion of faeces. Therefore, the patient started vancomycin treatment. The patient died from sepsis and pulmonary oedema 15 days later. Based on the ITT and PP analysis, we considered these two patients as FMT failures. Therefore, after these first two experiences with FMT, we decided to amend the FMT protocol to treat subjects with PMC with repeated faecal infusions every 3 days until the resolution of colitis was achieved.
FMT Group. In the FMT group, 13 of the 20 patients (65%) were cured after the first infusion of healthy donor faeces; none of these 13 subjects were diagnosed with PMC. The seven remaining patients were diagnosed with PMC; six of these patients received multiple infusions (four patients received two infusions; one patient received three infusions; and one underwent four infusions), and one patient received only one infusion. Overall, five of the seven patients with PMC were cured, while two had experienced a recurrence. These two subjects who received one or two infusions (the latter with an interval of 1 week) subsequently died from apparent C. difficile-related clinical complications. All five patients with PMC who were cured received a faecal infusion procedure every 3 days until the resolution of colitis was achieved. In these patients, we were able to observe the progressive disappearance of pseudo-membranes with the endoscope.
Overall, donor faeces cured 18 of the 20 patients (90%). At the time of writing this paper (October 2014), all cured FMT patients are still living with the exception of one patient who died 8 months after discharge following a heart attack.
Vancomycin Group. Five of the 19 patients (26%) were cured. Two patients were refractory to the antibiotic treatment and died from C. difficile-related complications, whereas the remaining 12 patients had a C. difficile recurrence. The median time to recurrence was 10 days (range, 4–21 days) after the end of the vancomycin treatment. At the time of recurrence, the latter patients had been previously discharged home from the hospital after an initial resolution of symptoms, and therefore we were not able to offer them the faecal infusion. At the time of writing this paper, we contacted all of these patients by phone to determine their clinical conditions, and found that they underwent repeated cycles of antibiotic therapy (including vancomycin and metronidazole) against further recurrences of C. difficile infection after the end of the study: seven patients had resolution of symptoms (five of them with documented negative toxin test results) after 1–3 cycles of therapy (however, two of these subjects died 6 and 8 months after hospital discharge from severe heart failure and from prostate cancer-related complications, respectively); two patients died from unspecified causes 3 and 5 months after discharge without a clear resolution of C. difficile infection symptoms and without providing data on their C. difficile status; three patients were lost during follow-up.
Overall Outcome Analysis. Overall, FMT by colonoscopy achieved significantly higher remission rates of recurrent C. difficile infection compared to vancomycin treatment (90% vs. 26%, P < 0.0001 for both ITT and PP analysis) (Figure 2). For FMT vs. vancomycin treatment, the overall odds ratio of the cure rates was 25.2 [99.9% confidence interval (CI) from 1.26 to 502.30). At 5 and 10 weeks from the end of the treatments, 18 of the 20 patients in the infusion group had negative C. difficile stool toxins; the remaining two patients had a positive stool toxin within 1 week after the treatment. In the vancomycin group, three subjects were negative for stool toxin after 5 weeks, and five patients were negative after 10 weeks.
(Enlarge Image)
Figure 2.
Percentage of patients cured.
None of the cured patients had episodes of diarrhoea for causes not related to C. difficile infection during the study period.
Immediately after donor faeces infusion, 19 of the 20 (94%) patients had diarrhoea, and 12 of the 29 patients experienced (60%) bloating and abdominal cramping. In all patients, these symptoms resolved within 12 h. During follow-up, all patients who were treated with donor faeces returned to their alvus habits. No adverse events specifically relatable to the vancomycin regimen were reported.
Results
Patient Recruitment and Duration of the Trial
From July 2013 through June 2014, 39 patients (F = 23, M = 16, mean age 73 years) were randomly assigned to one of the following treatments: FMT (20 subjects, F = 12, M = 8, mean age: 71 years) or vancomycin regimen (19 subjects, F = 11, M = 8, mean age 75 years). No patient refused the proposed treatment. At the planned 1-year interim analysis, FMT showed a significantly higher efficacy than vancomycin. Therefore, after consulting an independent committee (including two internists and one gastroenterologist), the study was stopped when a total of 39 patients were recruited.
In 23 of the 39 (59%) patients, a positive toxin test before inclusion was confirmed by a positive C. difficile culture. All enrolled patients completed the study protocol.
Baseline demographic and clinical characteristics of the patients are provided in Table 1.
Donors
Most approved donors were relatives of the patients (16 subjects); in two cases, the donors were intimates and in another two FMT cases, the donor was unrelated because the patients had no relatives. The unrelated donor was a subject that had previously served as a donor for his relative. Therefore, faeces from a total of 18 donors were used to treat 20 subjects in the infusion group. A mean (±s.d.) of 152 ± 32 g of faeces was infused. The mean time from defecation to infusion was 3.8 ± 0.8 h.
Study Outcomes
The first two patients in the FMT group had PMC. One of these two subjects had a recurrence after 1 week after an initial resolution of symptoms and thus underwent another faecal infusion. Although with the second procedure, we noted a partial reduction in the presence of pseudo-membranes and initial symptom resolution, the patient had another recurrence after 5 days. Therefore, the patient was treated with vancomycin but died from sepsis after 1 week. The second patient with PMC was affected by severe cardiopathy; he was initially treated with a faecal infusion. After an apparent initial amelioration of diarrhoea with an objective reduction in the thickening of the colonic wall during the TC examination, the patient had a recurrence 5 days after the faecal infusion procedure. Due to the deterioration of the general clinical condition of this patient, we could not offer him a second infusion of faeces. Therefore, the patient started vancomycin treatment. The patient died from sepsis and pulmonary oedema 15 days later. Based on the ITT and PP analysis, we considered these two patients as FMT failures. Therefore, after these first two experiences with FMT, we decided to amend the FMT protocol to treat subjects with PMC with repeated faecal infusions every 3 days until the resolution of colitis was achieved.
FMT Group. In the FMT group, 13 of the 20 patients (65%) were cured after the first infusion of healthy donor faeces; none of these 13 subjects were diagnosed with PMC. The seven remaining patients were diagnosed with PMC; six of these patients received multiple infusions (four patients received two infusions; one patient received three infusions; and one underwent four infusions), and one patient received only one infusion. Overall, five of the seven patients with PMC were cured, while two had experienced a recurrence. These two subjects who received one or two infusions (the latter with an interval of 1 week) subsequently died from apparent C. difficile-related clinical complications. All five patients with PMC who were cured received a faecal infusion procedure every 3 days until the resolution of colitis was achieved. In these patients, we were able to observe the progressive disappearance of pseudo-membranes with the endoscope.
Overall, donor faeces cured 18 of the 20 patients (90%). At the time of writing this paper (October 2014), all cured FMT patients are still living with the exception of one patient who died 8 months after discharge following a heart attack.
Vancomycin Group. Five of the 19 patients (26%) were cured. Two patients were refractory to the antibiotic treatment and died from C. difficile-related complications, whereas the remaining 12 patients had a C. difficile recurrence. The median time to recurrence was 10 days (range, 4–21 days) after the end of the vancomycin treatment. At the time of recurrence, the latter patients had been previously discharged home from the hospital after an initial resolution of symptoms, and therefore we were not able to offer them the faecal infusion. At the time of writing this paper, we contacted all of these patients by phone to determine their clinical conditions, and found that they underwent repeated cycles of antibiotic therapy (including vancomycin and metronidazole) against further recurrences of C. difficile infection after the end of the study: seven patients had resolution of symptoms (five of them with documented negative toxin test results) after 1–3 cycles of therapy (however, two of these subjects died 6 and 8 months after hospital discharge from severe heart failure and from prostate cancer-related complications, respectively); two patients died from unspecified causes 3 and 5 months after discharge without a clear resolution of C. difficile infection symptoms and without providing data on their C. difficile status; three patients were lost during follow-up.
Overall Outcome Analysis. Overall, FMT by colonoscopy achieved significantly higher remission rates of recurrent C. difficile infection compared to vancomycin treatment (90% vs. 26%, P < 0.0001 for both ITT and PP analysis) (Figure 2). For FMT vs. vancomycin treatment, the overall odds ratio of the cure rates was 25.2 [99.9% confidence interval (CI) from 1.26 to 502.30). At 5 and 10 weeks from the end of the treatments, 18 of the 20 patients in the infusion group had negative C. difficile stool toxins; the remaining two patients had a positive stool toxin within 1 week after the treatment. In the vancomycin group, three subjects were negative for stool toxin after 5 weeks, and five patients were negative after 10 weeks.
(Enlarge Image)
Figure 2.
Percentage of patients cured.
None of the cured patients had episodes of diarrhoea for causes not related to C. difficile infection during the study period.
Adverse Events
Immediately after donor faeces infusion, 19 of the 20 (94%) patients had diarrhoea, and 12 of the 29 patients experienced (60%) bloating and abdominal cramping. In all patients, these symptoms resolved within 12 h. During follow-up, all patients who were treated with donor faeces returned to their alvus habits. No adverse events specifically relatable to the vancomycin regimen were reported.
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