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Diagnostic tests favoured to detect C. difficile infections (CDI) have undergone successive changes. The problem of over-diagnosis with polymerase chain reaction (PCR) testing is recognized in the clinical setting; here we discuss the parallel of the clinical trial setting. We summarize and discuss four examples of the impact of method used to diagnose CDI on clinical trial outcomes. Bezlotoxumab, a human monoclonal antibody neutralizing toxin B, was found to be protective against recurrent CDI (rCDI) in clinical trials. A post hoc analysis showed that the magnitude of the relative reduction in rCDI rates of bezlotoxumab over placebo in patients diagnosed with toxin-based testing was almost double that in patients diagnosed with PCR. SER-109, a microbiome therapeutic developed to prevent rCDI, showed promise in a phase 1b trial, but results were not replicated in a phase 2 trial in which diagnosis was in majority PCR-based. Surotomycin, an oral lipopeptide antibiotic, was found to be non-inferior to vancomycin in phase 2 study, but development was discontinued after unfavourable phase 3 results in which the majority of CDI were diagnosed by PCR. Finally, a C. difficile vaccine program for a toxoid vaccine developed by Sanofi/Pasteur was terminated after interim analysis of a phase 3 trial, in which CDI diagnosis was based solely on PCR. We highlighted the perils of using PCR alone in studies involving different aspects of C. difficile clinical research, including immunotherapies, microbiome-based therapies, treatments, and vaccines. The importance of designing C. difficile clinical trials with careful consideration to the diagnostic testing method cannot be overemphasized.

Summary Background Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. Methods In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Findings Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Interpretation Fidaxomicin could be an alternative treatment for infection with C difficile , with similar efficacy and safety to vancomycin. Funding Optimer Pharmaceuticals.

101 patients with Clostridium-difficile -associated diarrhoea or colitis were prospectively randomised to 10-day oral courses of metronidazole, 250 mg four times a day, or vancomycin, 500 mg four times a day. 7 did not complete the protocol and were dropped from analysis. Pseudomembranous colitis (PMC) was diagnosed after endoscopy in 33 patients. Of the remaining patients without PMC, 38 had both C difficile culture and cytotoxin and 23 had only culture evidence of C difficile. 52 evaluable patients received vancomycin and 42 received metronidazole. There were two treatment failures with metronidazole and none with vancomycin (p = 0·20); and two relapses with metronidazole versus six with vancomycin (p = 0·17). Treatment in 1 patient in each group was discontinued because of drug intolerance. Response and relapse rates of the 33 patients with PMC were no different from those of the remaining patients. Pharmacy cost for the dosage used was $387.48 to $520.00 for vancomycin and $11.84 for metronidazole. Metronidazole and vancomycin have equivalent efficacy and relapse rates and are tolerated to a similar extent by patients with C-difficile -related diarrhoea and colitis, but metronidazole is considerably more economical.