Detection of Clostridioides [formerly Clostridium] difficile (C difficile) toxins in fecal matter can lead to accurate diagnosis of C difficile infection (CDI), according to study results published in Open Forum Infectious Diseases.
Previous research suggests that patients with CDI who are diagnosed using polymerase chain reaction (PCR) testing may be less likely to respond to CDI treatment compared with patients diagnosed using a direct toxin-based test. The objective of this study was to examine the effect of different diagnostic methods for CDI on efficacy outcomes in phase 3 MODIFY I/II trials, in which participants received bezlotoxumab to treat primary and recurrent CDI (previously covered here; original study available here).
In this post hoc analysis of pooled data from MODIFY I/II trials, researchers assessed initial clinical cure and recurrent CDI in participants diagnosed at baseline using direct toxin-based tests including enzyme immunoassay/cell cytotoxicity assay or indirect methods including toxin gene PCR (tgPCR)/toxigenic culture. All test kits used had a labeled specificity of ≥94% with the capacity to detect the presence of C difficile toxin B or its cognate tcdB gene. This study included only patients who received bezlotoxumab or placebo during the MODIFY I/II trials.
The main efficacy end points in this study included initial clinical cure and recurrent CDI. Other efficacy end points included sustained cure, diarrhea recurrence, rehospitalization, fecal microbiota transplant, and all-cause mortality.
The integrated modified intent-to-treat population from MODIFY I/II consisted of 1554 patients who received bezlotoxumab (n=781) and placebo (n=773). Toxin gene PCR or toxigenic culture was used to diagnose 399 patients in the bezlotoxumab group and 382 patients in the placebo group, for a total of 781 patients diagnosed using these methods. Toxin enzyme immunoassay or cell cytotoxicity assay was used to diagnose 382 patients in the bezlotoxumab group and 391 patients in the placebo group, for a total of 773 patients diagnosed using these methods.
Results revealed that initial clinical cure rates were lower in patients who were diagnosed using toxin gene PCR or toxigenic culture (bezlotoxumab 78.4%; placebo 77.7%) vs those diagnosed with toxin enzyme immunoassay or cell cytotoxicity assay (bezlotoxumab 81.7%; placebo 82.9%). Compared with placebo, bezlotoxumab significantly reduced the rate of recurrent CDI regardless of the diagnostic method used, with an absolute difference of -15.4% (95% CI, -22.0% to -8.7%) and -9.7% (95% CI, -16.8% to -2.5%) in the toxin enzyme immunoassay or cell cytotoxicity assay and toxin gene PCR or toxigenic culture subgroups, respectively.
Further, the recurrent CDI rate tended to be lower among patients treated with bezlotoxumab and diagnosed by toxin enzyme immunoassay or cell cytotoxicity assay (17.6%) vs toxin gene PCR or toxigenic culture (23.6%; absolute difference -6.0%; 95% CI, -12.4% to 0.3%; relative difference -25.4%). In the placebo group, recurrent CDI was approximately 33% regardless of the diagnostic method used. The relative reduction in the rate of recurrent CDI for the bezlotoxumab vs placebo group was higher for toxin enzyme immunoassay or cell cytotoxicity assay at 46.6% vs 29.1% for toxin gene PCR or toxigenic culture.
This study was a post hoc analysis, and was not designed to assess the effect of diagnostic method on the efficacy of bezlotoxumab in CDI. In addition, multiple factors may have led to the observed difference in efficacy between diagnostic subgroups, such as undetermined cause of diarrhea recurrence.
The researchers concluded that the use of direct toxin-based tests to detect fecal C difficile toxins can lead to the accurate diagnosis of CDI and ensures that therapeutic efficacy is not underestimated.
Disclosure: This clinical trial was supported by Merck Sharp & Dohme Corp. Please see the original reference for a full list of authors’ disclosures.
Wilcox MH, Rahav G, Dubberke ER, et al. Influence of diagnostic method on outcomes in phase 3 clinical trials of bezlotoxumab for the prevention of recurrent Clostridioides difficile infection: a post hoc analysis of MODIFY I/II. Open Forum Infect Dis. 2019;6(8): ofz293.