Initial Cure

A single new RCT comparing metronidazole, vancomycin, and tolevamer was published in 2014.³⁷ Tolevamer was inferior to both metronidazole and vancomycin, and is not discussed further since it is not licensed by the U.S. Food and Drug Administration. The results of the metronidazole and vancomycin arms (n = 537) showed that vancomycin led to a significant increase in subjects achieving initial cure (81.1 percent versus 72.7 percent; P = .02). When combined with the three previous RCTs comparing metronidazole to vancomycin,^41-43 the percentage of subjects achieving initial cure was significantly higher among those receiving vancomycin (83.9 percent versus 75.7 percent; RR 1.08, 95% CI 1.02 – 1.15).

The second RCT identified in our update is a trial of fidaxomicin versus vancomycin (n = 509).³⁸ This study is the second of two studies that led to the approval of fidaxomicin for the treatment of CDI in the United States. Consistent with the first study, which was included in our original review, fidaxomicin performed similarly to vancomycin for the outcome of initial cure. Specifically, the percentage of subjects meeting initial cure did not differ significantly by treatment received (87.7 percent for fidaxomicin versus 86.8 percent for vancomycin; P = .79). Combining these results with those from the first study of fidaxomicin versus vancomycin⁴⁰ led to a similar finding of no significant difference in initial cure when stratified by treatment received (87.6 percent versus 85.6 percent; RR 1.02, 95% CI 0.98 – 1.07).

Recurrent CDI

The newly identified trial of metronidazole versus vancomycin³⁷ demonstrated no difference between the two agents for the outcome of recurrent CDI (20.6 percent versus 23.0 percent; P = .64). Similarly, when data from this study were pooled with the three previous RCTs comparing metronidazole versus vancomycin, no significant differences were observed (16.5 percent versus 18.7 percent; RR 0.89, 95% CI 0.65 – 1.23).

In contrast, the trial of fidaxomicin versus vancomycin demonstrated that use of fidaxomicin led to significantly fewer subjects having recurrent CDI (12.7 percent versus 26.9 percent; P = .002). Similarly, when pooled with the data from the prior study of fidaxomicin and vancomycin,⁴⁰ recurrence remained less likely after fidaxomicin treatment (14.1 percent versus 26.1 percent; RR 0.55, 95% CI 0.42 – 0.71).

Finally, the observational study noted similar recurrence rates after oral metronidazole and vancomycin (20.6 percent and 19.0 percent, respectively), but higher rates after intravenous metronidazole (50.0 percent; P = .007).

Appendix Table G2. Initial clinical cure: # subjects / # randomized (%) for vancomycin versus metronidazole

Appendix Figure G16. Initial clinical cure: vancomycin versus metronidazole

Appendix Table G3. Initial clinical cure: # subjects / # randomized (%) for fidaxomicin versus vancomycin

Appendix Figure G17. Initial clinical cure: vancomycin versus fidaxomicin

Appendix Table G4. Clinical recurrence: # subjects / # initially cured (%) for vancomycin versus metronidazole

Appendix Figure G18. Recurrence of CDI: metronidazole versus vancomycin

Appendix Table G5. Clinical recurrence: # subjects / # initially cured (%) for fidaxomicin versus vancomycin

Appendix Figure G19. Recurrence of CDI: vancomycin versus fidaxomicin

Appendix Table G6. Severe disease: # subjects / # (%)

FMT for Recurrent CDI

We identified 26 studies that addressed FMT for recurrent CDI of which three were small size RCTs and the remaining were observational. We identified two studies that included both recurrent and active CDI.^57,68 The studies included individuals between the ages of 7 and 90 years, with children included in one study. In 18 of the 21 studies, >55 percent of the participants were women. Two studies reported race and ethnicity distribution.^47,62 One of these studies enrolled 21 indivduals for FMT of which 74 percent were white, 22 percent black ,and 4 percent Asian.⁴⁷ The other study enrolled 26 individuals, 100 percent of whom were white.⁶² Most studies were small, enrolling 12 to 94 individuals. Followup was variable, and ranged from 3 weeks to 8 years. Outcomes reported were resolution of diarrhea or symptoms, recurrence. and adverse events.

The three RCTs are noteworthy. One unblinded, three-arm RCT, conducted in the Netherlands, enrolled 43 adults with recurrent CDI with mean age of 70, 43 percent women.⁵⁹ Patients were randomized to oral vancomycin, FMT, or vancomycin plus bowel lavage. Followup was 10 weeks and the endpoint was resolution of diarrhea. The study was stopped early due to a large difference in the FMT and comparator groups (81 percent versus 31 percent and 23 percent). FMT was administered via nasoduodenal tube. However, the CDI rate in the comparator groups was unusually low.

Cammarota and colleagues conducted an additional unblinded trial of FMT via colonoscopy versus a vancomycin regimen that was given for at least 3 weeks, with the latter half given in a pulsed fashion (dosed every 2-3 days).⁴⁴ In patients with pseudomembranous colitis, the FMT protocol was amended after two patients to give FMT infusions every 3 days until resolution of colitis, versus the single infusion given to patients with CDI without pseudomembranous colitis. This study enrolled 39 subjects, with a mean age of 73. The primary endpoint was resolution of diarrhea associated with CDI at 10 weeks after the end of treatment. When analyzed by resolution after a single course of treatment (FMT or vancomycin), 65 percent of subjects had resolution of diarrhea with FMT, versus 26 percent with vancomycin. The authors noted that administering multiple courses of FMT increased the success rate to 90 percent in the FMT group and that multiple antibiotic courses increased the success rate to 53 percent in the vancomycin group. This study was also stopped early after an interim analysis.

Youngster and colleagues conducted an unblinded RCT that randomized 20 individuals with recurrent CDI, with mean age of 54, to colonoscopic or nasogastric administration of FMT.⁵⁴ The study endpoint was resolution of diarrhea without relapse within 8 weeks. The authors found no difference between the two modalities of FMT administration.

Appendix Figure G20. Resolution of symptoms after initial FMT for recurrent CDI, all routes

Appendix Table G7. Resolution of symptoms after initial FMT for recurrent CDI

FMT for Refractory CDI

Three studies reported outcomes for FMT in individuals with refractory CDI (defined as an episode that did not respond to antibiotic treatment). All were from case series, totaling 19 individuals.^46,53,64 Overall, there was insufficient strength of evidence supporting the role of FMT in refractory CDI. Unfortunately, few FMT studies provided detailed patient information to identify whether included patients could be considered refractory.

Appendix Table G8. Resolution of symptoms after initial FMT for recurrent CDI

Probiotics for CDI

We identified a total of 18 studies that reported use of probiotics as adjunctive treatment for CDI: nine RCTs and one observational study were newly identified, while seven RCTs were included in the prior report. With the plethora of RCTs to provide a best evidence base, the observational study will not be discussed further.

Probiotics were administered as an adjunct to standard antibiotic treatment for CDI in all the studies. All studies included adults with mean reported age of 50 to 77 years. The studies enrolled 40 to 2981 subjects. The probiotics tested were lactobacilli species in six studies, sacchromyces species (S. boulardii) in six studies, and multiorganism in five studies: both lactobacillus and saccharomyces species in one study, lactobacillus and bifidobacterium in two studies, a four-strain preparation of L. acidophilus, L. paracasei, and bifidobacterium in one study, and VSL#3 in one study. VSL#3 contained Bifidobacterium breve, Bidfidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus, and Streptococcus thermophiles. The comparator was placebo in 16 studies and standard care or no treatment in one study each. In four studies the probiotic was continued for the duration of antiobiotic therapy,^78-80,83 while in the others, the probiotic was continued for 3 to 21 days beyond antibiotic administration. Study endpoint was diagnosis of CDI and followup was limited, typically ranging from 7 days to 4 weeks, with two RCTs extending followup to 12 weeks.

For quantitative analysis, we categorized probiotics as single organism strains (lactobacillus species), S.boulardii, and those that contained multiple organisms. Overall, we found low-strength evidence that probiotics containing only lactobacillus organisms or multiple organisms are more effective than placebo in preventing an acute episode of CDI. We found low-strength evidence that probiotics containing S.boulardii given as adjunct to standard antimicrobial therapy, are comparable with placebo in preventing an episode of CDI.

Appendix Figure G21. Single organism probiotics for prevention of CDI-associated diarrhea

Appendix Table G9. Single organism probiotics for prevention of CDI-associated diarrhea

Appendix Figure G22. S boulardii for prevention of CDI-associated diarrhea

Appendix Table G10. S. boulardii probiotics for prevention of CDI-associated diarrhea

Appendix Figure G23. Multi-organism probiotics for prevention of CDI-associated diarrhea

Appendix Table G11. Multi-organism probiotics for prevention of CDI-associated diarrhea