Researchers Identify Biomarkers, Clinical Factors for C Difficile Infection Risk

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The overall 90-day cumulative incidences of a first CDI episode was 1.9%.

New research shows a handful of biomarkers and clinical characteristics can help clinicians identify high risk individuals for Clostridioides difficile infections (CDI).

A team, led by Cornelis H. van Werkhoven, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, assessed the potential clinical characteristics and biomarkers to predict C difficile infections in patients receiving newly initiated antibiotic treatment with penicillin along with a beta-lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones, or clindamycin.

“Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection,” the authors wrote.

The Study

In the prospective, observational, cohort study, the researchers examined 1007 patients at least 50 years old from 34 European hospitals in order to identify biomarkers and clinical characteristics that make it likely to predict C difficile infections. The median age was 70 years old, with 58.8% (n = 592) of the patient population male.

In addition, 172 individuals did not complete the follow-up, 86 of which died after a median of 20 days and 86 of which withdrew their consent or were lost to follow-up after a median of 5 days.

The majority of patients (93%) received only 1 of the 5 antibiotic classes on day, with penicillin with a beta-lactamase inhibitor being the most frequent.

C Difficile Incidence Rates

The overall 90-day cumulative incidences of a first CDI episode was 1.9% (95% CI, 1.1-3.0).

The researchers did identify a handful of factors that helped to predict an increased CDI risk, including carbapenem treatment (HR, 5.3; 95% CI, 1.7-16.6), toxigenic C. difficile rectal carriage (HR, 10.3; 95% CI, 3.2-33.1), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (HR, 5.4; 95% CI, 2.1-18.7), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (HR, 9.7; 95% CI, 3.2-29.7).

However, normalized urinary 3-indoxyl sulfate levels did not predict an increased C difficile infection risk.

A total of 135 participants reported 176 antibiotic-associated diarrhea (AAD) episodes, of which 114 episodes in 100 participants occurred within 28 days, while the cumulative incidence of AAD within 28 and 90 days was 10.5% (95% CI, 8.6–12.5) and 14.6% (95% CI, 12.4–17.0), respectively.

In 48 AAD episodes, there was no fecal sample was obtained for diagnosis of CDI, mainly due to episodes being reported too late.


“Although all evaluated antibiotic classes have been associated with CDI, in our study, only patients treated with carbapenems had a threefold increased risk of AAD and an almost fivefold increased risk of CDI within 90 days as compared to patients not receiving carbapenems at baseline,” the authors wrote. “The higher incidence in patients receiving carbapenems may be due to the broader antimicrobial activity spectrum resulting in more disruption of the intestinal microbiota, or to differences in baseline risk factors in patients receiving carbapenems compared to those receiving other antibiotics.”

CDI is considered the leading cause of infectious healthcare-related diarrhea globally. While different medical interventions such as vaccines, probiotics, and agents neutralizing antibiotic residuals in the colon are being developed, they often require data from pivotal trials demonstrating clinical efficacy prior to regulatory approval.

The study, “Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics,” was published online in Nature Communications.