Risk Stratification, Testing, and Treatment in Recurrent Clostridioides difficile

A new JAMA Insights review synthesizes evidence on recurrent Clostridioides difficile infection (rCDI), explaining how gut microbiome disruption enables toxin-mediated disease and drives relapse risk. The authors describe progression from colonization to symptomatic infection: C difficile spores, ubiquitous in health care and community settings, are ordinarily constrained by intact microbiota, bile-acid metabolism, and host immunity; antibiotic exposure and other perturbations permit bacterial overgrowth and toxin A/B production, epithelial injury, and colitis. Clinically, rCDI ranges from mild diarrhea to fulminant colitis, underscoring the need for accurate diagnosis, risk stratification, and relapse-prevention strategies.¹

In an email Q&A with Ed J Kuijper, MD, PhD, professor emeritus of experimental bacteriology at Leiden University Medical Center and head of its Experimental Microbiology and national C difficile reference laboratory, he discussed risk stratification and its implications for first-episode therapy and bezlotoxumab use, diagnostic algorithms to distinguish infection from colonization, sequencing of therapies after first and subsequent recurrences, and system-level prevention priorities.

Contagion: Which baseline factors most strongly predict recurrent CDI, and how should they guide first-episode therapy selection (fidaxomicin vs oral vancomycin) and consideration of bezlotoxumab?

Kuijper: Advanced age, a history of previous CDI and hospital-acquired CDI are commonly also associated with comorbidities (particularly renal impairment) and increase the risk for rCDI. In such patient populations, fidaxomicin is the preferred therapeutic option. Furthermore, various cost-effectiveness analyses have demonstrated that fidaxomicin use (more expensive than vancomycin) is economically justified for all hospitalized patients with CDI.

Contagion: What diagnostic algorithm best balances sensitivity and specificity to distinguish infection from colonization (eg, NAAT + toxin EIA), and how should NAAT-positive/toxin-negative results be managed?

Kuijper: The feces toxin EIA shows that C difficile (or its spores) is not only present but has also actively proliferates and producing toxins. This is a clear test result that should be used by the physician to start an anti-CDI treatment. However if the tests result come availabe and the patient has no diarrhea anymore, treatment is not recommend asspontaneous recovery may occur. NAAT+Toxin- is a difficult group. Is it only the presence of low amounts of inactiveC difficile cells and spores, or does the EIA fails because of the low not detectable amount of fecal toxins? Though guidelines generally advise against repeat testing, it may be an option to ask for rapid test if the clinical condtion has also been deteriorated.In this NAAT+Toxin- subgroup, the most critical step is to exclude alternative diagnoses, such as inflammatory bowel disease (IBD) or infections caused by other enteropathogenic bacteria or viruses.

Contagion: After a first and subsequent recurrence, how do you prioritize fidaxomicin (standard vs extended-pulsed), tapered/pulsed vancomycin, microbiota-based therapeutics, and bezlotoxumab, and what key safety/monitoring issues apply?

Kuijper: Fidaxomicin is the preferred treatment option for the first recurrence of CDI. It is commonly administered as an extended-pulsed regimen, which allows residual bacterial spores to germinate during the fidaxomicin-free intervals and subsequently be eliminated upon re-exposure to the antibiotic. Unlike vancomycin, fidaxomicin exhibits some activity against C difficile spores, although the supporting evidence remains limited.

In contrast, tapered or pulsed vancomycin regimens have not been rigorously studied and are largely based on expert opinion. A major drawback of prolonged vancomycin therapy is its profound disruption of the gut microbiota, which promotes the overgrowth of resistant bacteria, Gram-negative pathogens, and fungi, potentially leading to secondary infections.

Microbiota-based therapeutics are strongly recommended after three CDI episodes (i.e., two recurrences), although upcoming studies are expected to evaluate their use at earlier disease stages. The discontinuation of bezlotoxumab is unfortunate; however, new monoclonal antibodies targeting toxin B are currently under development and may serve as potential replacements.

Contagion: Which prevention strategies have the strongest evidence for reducing rCDI at the system level (eg, stewardship triggers, targeted prophylaxis, PPI deprescribing, environmental cleaning), and what high-value research gaps remain?

Kuijper: At the system level, it is mainly antibiotic stewardshipt that drives the development of CDI.Antistewardship efforts should address not only the decision to initiate or withhold antibiotic therapy (ie, indication) but also the optimal choice of agent and appropriate duration of treatment. Environmental cleaning with sporicidal agents is essential in outbreak settings but provides limited benefit in endemic situations.

Targeted prophylactic strategies for patients at increased risk of CDI, particularly those based on microbiota restoration, represent one of the most promising emerging approaches. Live biotherapeutic products (LBPs) such as VE303—a defined consortium of eight bacterial strains designed to prevent C difficile colonization—are currently under clinical investigation.

Disease severity tracks with fecal toxin concentrations, which correlate with higher risks of severe outcomes, recurrence, and mortality. In US surveillance data (CDC 2022), most cases present as mild infection, while approximately 6% require intensive care for fulminant colitis and about 2% result in death, underscoring the ongoing clinical burden and the need for prevention and relapse-mitigation strategies. The review offers a concise framework linking pathophysiology to bedside assessment: identify patients with recent antibiotic exposure or other microbiome-disrupting factors, recognize that toxin levels reflect severity and recurrence risk, and anticipate a wide severity range from uncomplicated diarrhea to surgical emergencies.¹

Reference

​​van Prehn J, Kuijper EJ, Dubberke ER. Recurrent Clostridioides difficile Infections. JAMA. Published online October 20, 2025. doi:10.1001/jama.2025.18089