Broad-spectrum antibiotic use increases the risk of Clostridioides difficile infection (CDI), with recurrence rates varying by antibiotic type, spectrum, and treatment duration. We assessed CDI recurrence risk using the days of antibiotic spectrum coverage (DASC) score, considering antibiotic spectrum and use duration.

We retrospectively analyzed patients with hospital-acquired CDI. A logistic regression analysis was used to evaluate CDI recurrence, incorporating three variables: DASC score prior to CDI diagnosis, type of anti-CDI drugs, or DASC score after CDI diagnosis.

Overall, 246 patients were included, with 31 (12.6 %) cases of recurrence. Median DASC scores within 30 days prior to CDI diagnosis were higher in the recurrent group than in the non-recurrent group (128 [interquartile range: 106-217] vs. 80 [interquartile range: 39-142], p < 0.01). Using the lowest quartile of DASC scores as the reference, the analysis indicated higher relative risks of CDI recurrence in the upper quartiles. However, daily DASC scores post-CDI diagnosis did not correlate with recurrence. Compared to metronidazole, fidaxomicin lowered the risk of CDI recurrence (relative risk 0.2, 95 % confidence interval: 0.1-0.8, p = 0.03).

The DASC score within 30 days prior to CDI diagnosis appears to be a predictive risk factor for CDI recurrence.

We aimed to determine the impact of prior antimicrobial treatment on recurrent Clostridioides difficile infection (CDI) based on days of antibiotic spectrum coverage (DASC) and predict the risk of recurrence to guide the selection of appropriate initial therapeutic agents.

We assessed the antimicrobial treatment administered to 195 patients with a history of CDI for 28 days before testing positive for C. difficile using DASC and illness severity using ATLAS scores. We determined DASC cutoff values and combined them with relevant factors in ATLAS to determine an association with CDI recurrence.

Forty-four patients had recurrences of C. difficile infection. The median (interquartile range, IQR) DASC value was significantly higher in the group with recurrent CDI (78 [50-128]) than without (48 [12-99]; p = 0.01). Cutoff values of 36 and 66 for DASC were determined using receiver operating characteristic (ROC) curves. Age and serum creatinine were associated with CDI recurrence according to ATLAS scores. We assessed the risk of recurrence by combining age, serum creatinine, and DASC scores. A scoring system was created by assigning each variable a score from 0 to 2. The area under the ROC curve for this scoring system was 0.70.

Assessing antimicrobial treatment using DASC before CDI can predict recurrence and should facilitate the selection of initial therapy for CDI.

Recurrent Clostridioides difficile infection (CDI) is primarily driven by antibiotic-induced disruption of the indigenous intestinal microbiota. Restoration of microbiota through fecal microbiota transplantation (FMT) is effective in preventing subsequent CDI, although this effect is attenuated with additional antibiotic exposure. The aim of this study was to identify the risk factors for recurrent antibiotic administration after FMT.

This is a prospective cohort of patients who were administered FMT for recurrent CDI from 1 July 2019 through 23 November 2023 across 6 institutions in the United States. Providers collected de-identified data at the time of FMT administration and in the months post-FMT administration.

The analysis included 448 patients. Risk factors for non-CDI antibiotic administration within 2 months of FMT included immunocompromised status (odds ratio [OR], 2.2 [95% confidence interval {CI}, 1.1-4.4]; P = .02), >3 non-CDI antibiotic courses pre-FMT (OR, 3.1 [95% CI, 1.4-6.8]; P = .006), and prior hospitalization for CDI (OR, 2.0 [95% CI, 1.1-3.8]; P = .02). The most common indications for non-CDI antibiotic administration post-FMT were urinary tract infections, respiratory infections, and procedure prophylaxis.

Non-CDI antibiotic exposure significantly increases the risk of CDI recurrence post-FMT. Risk factors for non-CDI antibiotic administration within 2 months of FMT include immunocompromised status, multiple prior non-CDI antibiotics, and prior hospitalization for CDI. These individuals may benefit from additional or modified recurrent CDI prevention strategies.

Background/Objectives:Clostridioides difficile infection (CDI) poses a significant healthcare challenge, with recurrence rates reaching 30%, leading to substantial morbidity and costs. Fidaxomicin (FDX) and bezlotoxumab (BEZ) have shown potential in reducing recurrence; however, real-world data on the efficacy of their combination in high-risk CDI patients remain limited. This study aimed to evaluate the efficacy and safety of FDX + BEZ compared with FDX alone in CDI patients with recurrence risk factors. Methods: CDI patients with ≥two recurrence risk factors treated with FDX alone or FDX + BEZ were analyzed. Sixteen factors were evaluated as risk factors for recurrent CDI based on findings from previous studies. Patients with FDX treatment duration <10 days or other CDI treatment prior to FDX were excluded. Outcomes included recurrence within 2 months, global and clinical cure rates, and adverse events. Univariate and multivariate analyses were performed to evaluate efficacy. Results: Among 82 patients, the FDX + BEZ group (n = 30) demonstrated significantly higher global (86.7% vs. 65.4%; p < 0.05) and clinical cure rates (90.0% vs. 69.2%; p < 0.05) compared with the FDX-alone group (n = 52), despite more severe cases in the combination group. Recurrence rates were non-significantly lower in the FDX + BEZ group (3.3% vs. 11.5%). Combination therapy also accelerated diarrhea resolution without additional adverse events. Multivariate analysis identified FDX + BEZ as significantly associated with improved clinical cure (adjusted odds ratio 4.167; 95% CI: 1.029-16.885). Conclusions: FDX + BEZ therapy offers superior efficacy and safety in CDI patients with recurrence risk factors, presenting a promising strategy for optimizing CDI management.

Increasing evidence suggests that the gut microbiome is important in immune system function and influences the risk of periprosthetic joint infection (PJI) after total knee arthroplasty (TKA). A Clostridium difficile infection (CDI) is an indicator of poor gut microbiome health. However, no prior studies have evaluated the independent risk of CDI on the rates of PJI after TKA.

Patients undergoing TKA from 2010 to 2021 were identified in a patient claims database (n = 1,416,362). Patients who had a history of CDI within 2 years prior to TKA (n = 5,170) were propensity-matched on a 1:4 basis to those who did not have a diagnosis of CDI. The exposed CDI cohort was also stratified into four groups by time of CDI before TKA (0 to 3 months, 3 to 6 months, 6 to 12 months, and 1 to 2 years). The risk of PJI within 2 years following TKA was compared between the exposed and control cohorts. Logistic regressions were used to evaluate the association of CDI occurring in each time interval prior to TKA and PJI after TKA.

A CDI within 2 years prior to TKA was independently associated with higher odds of PJI (odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.91 to 2.36). In addition, we observed a stepwise increase in the risk of PJI by the timing of preoperative CDI infection, with patients who had a diagnosis of CDI within 3 months of their primary TKA exhibiting the highest odds of developing PJI (OR: 4.19; 95% CI: 3.51 to 5.02). Additionally, patients who had a diagnosis of CDI within 2 years of undergoing primary TKA were significantly more likely to experience a subsequent episode of CDI at the latest follow-up (OR: 25.9; 95% CI: 22.3 to 30.1).

A CDI prior to TKA is an independent risk factor for PJI. Closer proximity of CDI to surgery is associated with a "dose-dependent" increased PJI risk. Surgeons should consider delaying TKA until a minimum of 1 year after a diagnosis of CDI.

Clostridioides difficile infection (CDI) is a common and often nosocomial infection associated with increased mortality and morbidity. Antibiotic use is the most important modifiable risk factor, but many patients require empiric antibiotics. We estimated the increased risk of hospital-onset CDI with one daily dose-equivalent (DDE) of various empiric antibiotics compared to management without that daily dose-equivalent.

Using a multicenter retrospective cohort of adults admitted between March 2, 2020 and February 11, 2021 for the treatment of SARS-CoV-2, we used a series of three-level logistic regression models to estimate the probability of receiving each of several antibiotics of interest. For each antibiotic, we then limited our data set to patient-days at intermediate probability of receipt and used augmented inverse-probability weighted models to estimate the average treatment effect of one daily dose-equivalent, compared to management without that daily dose-equivalent, on the probability of hospital-onset CDI.

In 24,406 patient-days at intermediate probability of receipt, parenteral vancomycin increased risk of hospital-onset CDI, with an average treatment effect of 0.0096 cases per daily dose-equivalent (95% CI: 0.0053-0.0138). In 38,003 patient-days at intermediate probability of receipt, cefepime also increased subsequent CDI risk, with an estimated effect of 0.0074 more cases per daily dose-equivalent (95% CI: 0.0022-0.0126).

Among common empiric antibiotics, parenteral vancomycin and cefepime appeared to increase risk of hospital-onset CDI. Causal inference observational study designs can be used to estimate patient-level harms of interventions such as empiric antimicrobials.

Microbiome science has evolved rapidly in the past decade, with high-profile publications suggesting that the gut microbiome is a causal determinant of human health. This has led to the emergence of microbiome-focused biotechnology companies and pharmaceutical company investment in the research and development of gut-derived therapeutics. Despite the early promise of this field, the first generation of microbiome-derived therapeutics (faecal microbiota products) have only recently been approved for clinical use. Next-generation therapies based on readily culturable and as-yet-unculturable colonic bacterial species (with the latter estimated to comprise 63% of all detected species) have not yet progressed to pivotal phase 3 trials. This reflects the many challenges involved in developing a new class of drugs in an evolving field. Here we discuss the evolution of the live biotherapeutics field over the past decade, from the development of first-generation products to the emergence of rationally designed second- and third-generation live biotherapeutics. Finally, we present our outlook for the future of this field.

Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea. The infection is associated with a high mortality rate and risk of recurrence. We assessed risk factors for death or recurrent CDI (CDI) in patients with diabetes mellitus (DM).

This retrospective cohort study was conducted at a single institution from 2019 to 2020. CDI was defined as a positive toxin assay for C. difficile. CDI was defined as a repeat positive toxin assay within ≤ 60 days of stopping CDI treatment. Logistic regression models were used to identify risk factors for CDI-related mortality, recurrence, and the combined outcome of mortality and recurrence.

Of the 252 enrolled patients with CDI, 19% had DM. Only 49% of patients with DM fully recovered after the first CDI occurrence, whereas 69% of patients without diabetes fully recovered (p = 0.021); 23% of patients with DM vs. 17% of patients without DM had recurrences (p = 0.200); and 23% of patients with DM vs. 15% of patients without DM died (p = 0.169). DM was associated with mortality (OR 2.75, 95% CI 0.94-8.06) and the combined outcome (OR 2.10, 95% CI 1.05-4.18). Nosocomial transmission, immunosuppression, CKD, and age were associated with mortality.

Diabetes is associated with a worse prognosis in patients with CDI. Prevention efforts should be optimized in patients with diabetes by reducing CDI transmission and avoiding nonessential medications, such as PPIs or antibiotics when they are not necessary. [Figure: see text].

Fever and diarrhea are the common symptoms of Clostridioides difficile infection (CDI); however, pseudomembranous enteritis, megacolonization, and paralytic ileus have been observed in severe cases. C. difficile spores are resistant to several types of disinfectants. Thus, they are often the causative pathogens of healthcare-associated infections. Rapid diagnostic tests based on glutamate dehydrogenase and toxins are the mainstay of CDI laboratory diagnosis owing to their simplicity. CDI can be diagnosed with high specificity using the nucleic acid amplification test, a genetic test for C. difficile toxins. The risk factors for CDI include age ≥65 years; history of antimicrobial use; previous hospitalization; history of gastrointestinal surgery, chronic kidney disease, or inflammatory bowel disease; nasal tube feeding; and use of proton pump inhibitors and histamine H2 receptor antagonists. The risk of CDI development persists even 1 year after discontinuation of proton pump inhibitor use. Furthermore, colorectal surgery and radical cystectomy with urinary diversion are associated with high incidences of postoperative CDI. The choice of therapeutic agent depends on the severity of the disease and recurrence. However, a combination of oral or nasogastric vancomycin, intracolonic vancomycin, and intravenous metronidazole can be considered in patients with toxic megacolonization and paralytic ileus. In January 2024, the European Committee on Antimicrobial Susceptibility Testing established a breakpoint for fidaxomicin (minimum inhibitory concentration breakpoint > 2 mg/L) against C. difficile. Rapid progress has been achieved in CDI treatment. Thus, multidisciplinary teams must collaborate to diagnose, treat, and control CDI.

Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo. VE303 organisms robustly colonized the gut in the high-dose group and were among the top taxa associated with non-recurrence. Multi-omic modeling identified antibiotic history, baseline stool metabolites and serum cytokines as predictors of both on-study CDI recurrence and VE303 colonization. VE303 potentiated early recovery of the host microbiome and metabolites with increases in short-chain fatty acids, secondary bile acids and bile salt hydrolase genes after antibiotic treatment for CDI, which is considered important to prevent CDI recurrences. These results support the idea that VE303 promotes efficacy in rCDI through multiple mechanisms.

Clostridioides difficile is an urgent public health threat that affects approximately half a million patients annually in the United States. Despite concerted efforts aimed at the prevention of Clostridioides difficile infection (CDI), it remains a leading cause of healthcare-associated infections. CDI is associated with significant clinical, social, and economic burdens. Therefore, it is imperative to provide optimal and timely therapy for CDI. We conducted a systematic literature review and offer treatment recommendations based on available evidence for the treatment and prevention of CDI.

Antibiotics are a strong risk factor for Clostridioides difficile infection (CDI), and CDI incidence is often measured as an important outcome metric for antimicrobial stewardship interventions aiming to reduce antibiotic use. However, risk of CDI from antibiotics varies by agent and dependent on the intensity (ie, spectrum and duration) of antibiotic therapy. Thus, the impact of stewardship interventions on CDI incidence is variable, and understanding this risk requires a more granular measure of intensity of therapy than traditionally used measures like days of therapy (DOT).

We performed a retrospective cohort study to measure the independent association between intensity of antibiotic therapy, as measured by the antibiotic spectrum index (ASI), and hospital-associated CDI (HA-CDI) at a large academic medical center between January 2018 and March 2020. We constructed a marginal Poisson regression model to generate adjusted relative risks for a unit increase in ASI per antibiotic day.

We included 35 457 inpatient encounters in our cohort. Sixty-eight percent of patients received at least 1 antibiotic. We identified 128 HA-CDI cases, which corresponds to an incidence rate of 4.1 cases per 10 000 patient-days. After adjusting for known confounders, each additional unit increase in ASI per antibiotic day was associated with 1.09 times the risk of HA-CDI (relative risk = 1.09; 95% CI: 1.06-1.13).

The ASI was strongly associated with HA-CDI and could be a useful tool in evaluating the impact of antibiotic stewardship on HA-CDI rates, providing more granular information than the more commonly used DOT.

To compare rates of Clostridioides difficile infection (CDI) recurrence following initial occurrence treated with tapered enteral vancomycin compared to standard vancomycin.

Retrospective cohort study.

Community health system.

Adults ≥18 years of age hospitalized with positive C. difficile polymerase chain reaction or toxin enzyme immunoassay who were prescribed either standard 10-14 days of enteral vancomycin four times daily or a 12-week tapered vancomycin regimen.

Retrospective propensity score pair matched cohort study. Groups were matched based on age < or ≥ 65 years and receipt of non-C. difficile antibiotics during hospitalization or within 6 months post-discharge. Recurrence rates were analyzed via logistic regression conditioned on matched pairs and reported as conditional odds ratios. The primary outcome was recurrence rates compared between standard vancomycin versus tapered vancomycin for treatment of initial CDI.

The CDI recurrence rate at 6 months was 5.3% (4/75) in the taper cohort versus 28% (21/75) in the standard vancomycin cohort. The median time to CDI recurrence was 115 days versus 20 days in the taper and standard vancomycin cohorts, respectively. When adjusted for matching, patients in the taper arm were less likely to experience CDI recurrence at 6 months when compared to standard vancomycin (cOR = 0.19, 95% CI 0.07-0.56, p < 0.002).

Larger prospective trials are needed to elucidate the clinical utility of tapered oral vancomycin as a treatment option to achieve sustained clinical cure in first occurrences of CDI.

Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI.

To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities.

VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24.

TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression.

VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients.

ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

There are limited data on the contemporary epidemiology of recurrent Clostridioides difficile infection (CDI) among hematopoietic cell transplant (HCT) recipients. We aimed to determine the incidence, risk factors, and outcomes for recurrent CDI among HCT recipients.

We conducted a retrospective study of adult HCT recipients between 2012 and 2021 diagnosed with index CDI between HCT day -7 and +100. Recurrent CDI was defined as new symptoms and a positive test within 12 weeks after treatment for index CDI. Cox proportional hazards models were used to investigate associations between prespecified variables (age, neutropenia, exposure to antibiotics with antianaerobic coverage, cytomegalovirus viremia/disease, and metronidazole monotherapy) and recurrent infection, presented as hazard ratios with 95% confidence intervals (CI).

Of 3479 HCT recipients, 416 (12%) had index CDI and were treated with oral vancomycin (31%), metronidazole (41%), oral vancomycin and metronidazole (29%). Of 381 patients eligible for recurrent CDI analysis, 35 had recurrent infection; cumulative incidence was 10% (95% CI, 7-13) at 12 weeks. In the 14 days after recurrence, 2/25 (8%) patients required hospital admission; none died within 30 days. Metronidazole monotherapy for treatment of index CDI was associated with an increased rate of recurrence (adjusted hazard ratio, 2.0; 95% CI, 1.0-4.0; P = .048).

Recurrent CDI occurred in 10% of HCT recipients in the early posttransplant period and was associated with use of metronidazole. Further study is needed to characterize risk factors for recurrent CDI among HCT recipients to guide use of agents aimed at preventing recurrence.

Clostridioides difficile is a bacterium that causes life-threatening intestinal infections. Infection symptoms are mediated by a toxin secreted by the bacterium. Toxin pathogenesis is modulated by the intracellular molecule, inositol-hexakisphosphate (IP6). IP6 binds to a cysteine protease domain (CPD) on the toxin, inducing autoproteolysis, which liberates a virulence factor in the cell cytosol. We developed second-generation IP6 analogs designed to induce autoproteolysis in the gut lumen, prior to toxin uptake, circumventing pathogenesis. We synthesized a panel of thiophosphate-/sulfate-containing IP6 analogs and characterized their toxin binding affinity, autoproteolysis induction, and cation interactions. Our top candidate was soluble in extracellular cation concentrations, unlike IP6. The IP6 analogs were more negatively charged than IP6, which improved affinity and stabilization of the CPD, enhancing toxin autoproteolysis. Our data illustrate the optimization of IP6 with thiophosphate biomimetic which are more capable of inducing toxin autoproteolysis than the native ligand, warranting further studies in vivo.

Advanced age has been widely identified as a risk factor for recurrent Clostridioides difficile infection (CDI), but most related studies were performed before the introduction of novel therapies. The aim of this study was to compare CDI characteristics and outcomes in patients over and under 80 years old with CDI and their outcomes in the era of new treatments.

This was a retrospective cohort study of patients diagnosed with CDI from January 2021 to December 2022 in an academic hospital. We compared recurrence and mortality at 12 weeks after the end of treatment. An extension of the Fine and Grey model adjusted for competing events was used to assess the effect of age on recurrence.

Four hundred seventy-six patients were considered to have CDI (320 in patients <80 years and 156 in ≥80 years). CDI in older patients was more frequently healthcare-associated and was more severe. Although the Charlson index was almost identical between populations, comorbidities clearly differed. New treatments (bezlotoxumab, fidaxomicin and faecal microbiota transplantation) were more frequently used in older patients without statistical significance (41.3% vs. 33.4%, P = .053). There were 69 (14.5%) recurrences, with no differences by age group after adjusting for competing events. Mortality was greater in the oldest (35.3%) than in the youngest (13.1%); P < .001.

No differences in CDI recurrence rates were found between age groups. However, there was a high mortality rate in patients ≥80 years old, which emphasises the urgent need to improve the prevention and treatment of CDI in this group.

There is a paucity of data guiding treatment duration of oral vancomycin for Clostridiodes difficile infection (CDI) in patients requiring concomitant systemic antibiotics.

To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence.

In this retrospective cohort study, we evaluated adult hospitalized patients with an initial episode of CDI who were treated with vancomycin and who received overlapping systemic antibiotics for >72 hours. Outcomes of interest included CDI recurrence and isolation of vancomycin-resistant Enterococcus (VRE).

Among the 218 patients included, 36% received a standard duration and 64% received a prolonged duration of treatment for a median of 13 days (11-14) and 20 days (16-26), respectively. Patients who received a prolonged duration had a longer median duration of systemic antibiotic overlap with vancomycin (11 vs 8 days; P < .001) and significantly more carbapenem use and infectious disease consultation. Recurrence at 8 weeks (12% standard duration vs 8% prolonged duration; P = .367), recurrence at 6 months (15% standard duration vs 10% prolonged duration; P = .240), and VRE isolation (3% standard duration vs 9% prolonged duration; P = .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1).

Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.

Clostridioides difficile is the most common cause of healthcare-associated infection, and severe cases can result in significant complications. While anti-microbial therapy is central to infection management, adjunctive therapies may be utilised as preventative strategies.

This article aims to review updates in the epidemiology, diagnosis, and management, including treatment and prevention, of C. difficile infections.

A narrative review was performed to evaluate the current literature between 1986 and 2023.

The incidence of C. difficile infection remains significantly high in both hospital and community settings, though with an overall decline in recent years and similar surveillance estimates globally. Vancomycin and fidaxomicin remain the first line antibiotics for treatment of non-severe C. difficile infection, though due to lower recurrence rates, infectious disease society guidelines now favour use of fidaxomicin. Faecal microbiota transplantation should still be considered to prevent recurrent C. difficile infection. However, in the past year the field has had a significant advancement with the approval of the first two live biotherapeutic products-faecal microbiota spores-live brpk, an oral capsule preparation, and faecal microbiota live-jslm-both indicated for the prevention of recurrent C. difficile infection, with additional therapies on the horizon.

Although the prevalence of C. difficile infection remains high, there have been significant advances in the development of novel therapeutics and preventative measures following changes in recent practice guidelines, and will continue to evolve in the future.

Many factors have been associated with the risk of toxigenic C. difficile diarrhea (TCdD). This study derived and internally validated a multivariate model for estimating the risk of TCdD in patients with diarrhea using readily available clinical factors.

A random sample of 3,050 symptomatic emergency department or hospitalized patients undergoing testing for toxigenic C. difficile at a single teaching hospital between 2014 and 2018 was created. Unformed stool samples positive for both glutamate dehydrogenase antigen by enzyme immunoassay and tcdB gene by polymerase chain reaction were classified as TCdD positive. The TCdD Model was created using logistic regression and was modified to the TCdD Risk Score to facilitate its use.

8.1% of patients were TCdD positive. TCdD risk increased with abdominal pain (adjusted odds ratio 1.3; 95% CI, 1.0-1.8), previous C. difficile diarrhea (2.5, 1.1-6.1), and prior antibiotic exposure, especially when sampled in the emergency department (4.2, 2.5-7.0) versus the hospital (1.7, 1.3-2.3). TCdD risk also increased when testing occurred earlier during the hospitalization encounter, when age and white cell count increased concurrently, and with decreased eosinophil count. In internal validation, the TCdD Model had moderate discrimination (optimism-corrected C-statistic 0.65, 0.62-0.68) and good calibration (optimism-corrected Integrated Calibration Index [ICI] 0.017, 0.001-0.022). Performance decreased slightly for the TCdD Risk Score (C-statistic 0.63, 0.62-0.63; ICI 0.038, 0.004-0.038).

TCdD risk can be predicted using readily available clinical risk factors with modest accuracy.

Current models for predicting Clostridioides difficile infection (CDI) recurrence rates have a limited capacity to account for important risk factors. This study developed a clinical prediction rule for CDI recurrence.

This retrospective cohort study evaluated 209 patients with CDI at a university hospital in Japan. Logistic regression and receiver operating characteristic curve analyses were performed to identify potential predictors (age, sex, underlying diseases, antibiotic use, acid suppressants, immunosuppressants, CDI history) of CDI recurrence.

Forty-five patients developed recurrent CDI. Univariate analyses identified several significant recurrence predictors (enteral feeding, inflammatory bowel diseases [IBD], community-onset CDI, severe CDI). Enteral feeding (odds ratio: 3.87, 95% confidence interval: 1.75-8.56) and IBD (odds ratio: 7.08, 95% confidence interval: 1.28-39.06) were significant factors in the multivariate analysis. The CHIEF predictive scoring system was developed using 5 relevant variables (carbapenem use, hematologic malignancy, IBD, enteral feeding, fluoroquinolone use); the area under the receiver operating characteristic curve for the CHIEF score was 0.70.

The CHIEF score incorporates useful, clinically available factors and could help identify patients at risk of recurrent CDI.

These findings contribute to the understanding of risk factors associated with CDI recurrence and provide support for the development of prevention strategies.

Patients with cancer are vulnerable to Clostridioides difficile infection (CDI) due to their disease, treatment and regular hospital contact, yet if CDI-recurrence is more common remains unclear, and differences among cancer types remain unexplored.

This Swedish nationwide population-based cohort included all 43,150 individuals with recorded CDI (2006-2019) to assess CDI-recurrence in individuals with and without cancer, with binary multivariable logistic regression, stratified by anatomical location, and survival status.

Compared to those without cancer (N = 29,543), ongoing cancer (diagnosis < 12 months; N = 3,882) was associated with reduced recurrence (OR = 0.81, 95% CI 0.73-0.89), while there was no association with cancer history (diagnosis ≥ 12 months; N = 9,725). There was an increased 8-week all-cause mortality (Ongoing cancer: OR = 1.58, 95% CI 1.43-1.74; Cancer history: OR = 1.45, 95% CI 1.36-1.55) compared to those without cancer. Among CDI-survivors, those with ongoing cancer presented with a decreased odds of recurrence (OR = 0.84, 95% CI 0.76-0.94), compared to those without cancer history, with no association for those with cancer history (OR = 1.04, 95% CI 0.97-1.1). Large variations were seen across cancer types, with the highest observed proportion of recurrence in oral and mesothelial cancer, and the lowest for esophageal cancer, although no statistically significant OR were found.

The population-based study indicates that individuals with cancer may have fewerrecurrences than expected, yet variations by cancer type were large, and mortality was high.

To estimate the epidemiological and clinical burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England.

This retrospective study included adult patients diagnosed with CDI (community or hospital settings) over 2015-2019 from Clinical Practice Research Datalink and Hospital Episode Statistics databases. Incidences of CDI and rCDI were determined annually. Time to subsequent rCDI was estimated by Kaplan-Meier method. Rates of complications were assessed within 12 months from index episode. Association of risk factors with complications was evaluated using a Cox regression model.

A total of 52,443 CDI episodes were recorded among 36,913 patients. Of these, 75% were aged ≥65 years, 59% were women; 73% were treated in community settings. CDI incidence remained stable (111 episodes per 100,000 patients in 2019). Around 21% of patients had ≥1 rCDI. Sepsis (12%) was the most common complication, followed by colectomy and ulcerative colitis. Age, gender, comorbidities, rCDI, preindex medical procedures, hospitalizations and consultations, and CDI treatment in hospital, were found to increase the risk of complication.

CDI remains a concern in England. The study highlights the importance of managing primary and rCDI episodes via effective and improved therapies to prevent fatal complications.

Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in adults. Various C. difficile strains circulate currently, associated with different outcomes and antibiotic resistance profiles. However, most studies still focus on the reference strain 630 that does not circulate anymore, partly due to the lack of immunological tools to study current clinically important C. difficile PCR ribotypes. The goal of this study was to generate monoclonal antibodies recognizing various epidemic ribotypes of C. difficile. To do so, we immunized mice expressing human variable antibody genes with the Low Molecular Weight (LMW) subunit of the surface layer protein SlpA from various C. difficile strains. Monoclonal antibodies purified from hybridomas bound LMW with high-affinity and whole bacteria from current C. difficile ribotypes with different cross-specificities. This first collection of anti-C. difficile mAbs represent valuable tools for basic and clinical research.

Clostridioides difficile (C. difficile) is a predominant nosocomial infection, and guidelines for improving diagnosis and treatment were published in 2017. We conducted a single-center, retrospective 10-year cohort study of patients with primary C. difficile infectious disease (CDID) at the largest referral Lithuanian university hospital, aiming to evaluate the clinical and laboratory characteristics of CDID and their association with the outcomes, as well as implication of concordance with current Clinical Practice Guidelines. The study enrolled a total of 370 patients. Cases with non-concordant CDID treatment resulted in more CDID-related Intensive Care Unit (ICU) admissions (7.5 vs. 1.8%) and higher CDID-related mortality (13.0 vs. 1.8%) as well as 30-day all-cause mortality (61.0 vs. 36.1%) and a lower 30-day survival compared with CDID cases with concordant treatment (p < 0.05). Among cases defined by two criteria for severe CDID, only patients with non-concordant metronidazole treatment had refractory CDID (68.8 vs. 0.0%) compared with concordant vancomycin treatment. In the presence of non-concordant metronidazole treatment for severe CDID, only cases defined by two severity criteria had more CDID-related ICU admissions (18.8 vs. 0.0%) and higher CDID-related mortality (25.0 vs. 2.0%, p < 0.05) compared with cases defined by one criterion. Severe comorbidities and the continuation of concomitant antibiotics administered at CDID onset reduced (p < 0.05) the 30-day survival and increased (p = 0.053) 30-day all-cause mortality, with 57.6 vs. 10.7% and 52.0 vs. 25.0%, respectively. Conclusions: CDID treatment non-concordant with the guidelines was associated with various adverse outcomes. In CDID with leukocytes ≥ 15 × 109/L and serum creatinine level > 133 µmol/L (>1.5 mg/dL), enteral vancomycin should be used to avoid refractory response, as metronidazole use was associated with CDID-related ICU admission and CDID-related mortality. Severe comorbidities worsened the outcomes as they were associated with reduced 30-day survival. The continuation of concomitant antibiotic therapy increased 30-day all-cause mortality; thus, it needs to be reasonably justified, deescalated or stopped.

Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI.

Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline.

Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo.

In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Clostridioides difficile infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a growing medical problem. Data from real-life studies and one open label randomised clinical trial (RCT) suggest that secondary prophylaxis with oral vancomycin (SPV) during subsequent courses of systemic antibiotics is a promising approach for reducing the risk of CDI recurrence. Our aim is to confirm the role of SPV through a double-blind RCT.

We will perform a phase III, multicentre, placebo-controlled RCT (PREVAN trial) in a 2:1 ratio in favour of SPV (experimental treatment), in four tertiary care hospitals in Spain. Adult patients (≥18 years) with a previous history of CDI in the previous 180 days and with requirement for hospitalisation and systemic antibiotic therapy will be randomly allocated to receive either 125 mg of oral vancomycin or placebo every 6 hours for 10 days. Patients will be followed for 60 days after the end of treatment to verify a reduction in the rate of CDI recurrence in the experimental group. We assume a recurrence rate of 5% in the experimental group versus 25% in the placebo group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 104 subjects will be required in total (68 assigned to the SPV group and 34 to the placebo group).

Ethical approval has been obtained from the Ethic Committee for Research with medicinal products of the University Hospital '12 de Octubre' (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), which is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.

NCT05320068.

The objectives were to determine the risk factors for recurrent healthcare facility-associated Clostridioides difficile infection (HCF-CDI) in a high CDI incidence, low antibiotic use setting and to determine if length of cefotaxime exposure is a risk factor for recurrent HCF-CDI.

The risk factors for recurrent HCF-CDI were evaluated with a retrospective nested case control study based on chart reading. The risk factors were evaluated univariately and multivariately. Length of risk antibiotic exposure was evaluated further in a subanalysis.

Risk factors for recurrent HCF-CDI were renal insufficiency (25.4% of cases compared to 15.4% of controls p = 0.006) and metronidazole treatment of initial CDI episode (88.4% compared to 71.7% p = 0.01). Exposure to cefotaxime and risk for recurrent CDI showed a dose-dependent relationship (linear by linear p = 0.028).

Renal insufficiency and metronidazole treatment were independent risk factors for recurrent HCF-CDI in our setting. The relationship between cefotaxime exposure and risk for recurrent HCF-CDI, dose-dependent, could be evaluated further in a setting with high cefotaxime use.

Fecal microbiota transplantation (FMT) emerged as rescue treatment for multiply recurrent Clostridioides difficile infections (rCDIs) nonresponsive to standard therapy. However, estimation of FMT efficacy varies among different protocols and formulations, while placebo-controlled clinical trials have excluded most rCDI patients because of medical comorbidities. This study aimed to determine the safety and effectiveness of capsule FMT (cap-FMT) and colonoscopy FMT (colo-FMT) for rCDI using standardized products in a large, multicenter, prospective, real-world cohort.

Clinical outcomes and adverse events after FMT performed for rCDI at 6 sites were captured in a prospective registry. FMT was performed using 1 of 2 standardized formulations of microbiota manufactured by the University of Minnesota Microbiota Therapeutics Program, freeze-dried/encapsulated or frozen-thawed/liquid. The FMT administration route was determined by the treating physician. The rCDI cure rate was assessed at 1 and 2 months. Safety data were collected within the first 72 hours and at 1 and 2 months. Logistic regression was used to investigate factors associated with FMT failure.

A total of 301 FMTs were performed in 269 unique patients. Two-thirds were cap-FMT. CDI cure rates were 86% (95% CI, 82%-90%) at 1 month and 81% (95% CI, 75%-86%) at 2 months. There was no difference in the 1-month or 2-month cure rate between cap-FMT and colo-FMT. Cap-FMT recipients were older and less likely to be immunosuppressed or have inflammatory bowel disease. Patient factors of older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression. In addition, post-FMT antibiotic use was associated with FMT failure at 2 months. One serious adverse event was related to colonoscopy (aspiration pneumonia), otherwise no new safety signals were identified.

Cap-FMT using freeze-dried capsules has a similar safety and effectiveness profile compared with colo-FMT, without the procedural risks of colonoscopy. Although highly effective overall, patient selection is a key factor to optimizing FMT success.

Clostridioides difficile remains a problematic pathogen resulting in significant morbidity and mortality, especially for high-risk groups that include immunocompromised patients. Both the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA), as well as the American College of Gastroenterology (ACG) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recently provided guideline updates for C. difficile infection (CDI). In this narrative review, the authors reviewed available literature regarding the prevention or treatment of CDI in adults and focused on disagreements between the IDSA/SHEA and ACG guidelines, as well as articles that have been published since the updates. Several options for primary prophylaxis are available, including probiotics and antibiotics (vancomycin, fidaxomicin). The literature supporting fidaxomicin is currently quite limited. While there are more studies evaluating probiotics and vancomycin, the optimal patient populations and regimens for their use have yet to be defined. While the IDSA/SHEA guidelines discourage metronidazole use for mild CDI episodes, evidence exists that it may remain a reasonable option for these patients. Fidaxomicin has an advantage over vancomycin in reducing recurrences, but its use is limited by cost. Despite this, recent studies suggest fidaxomicin's cost-effectiveness as a first-line therapy, though this is highly dependent on institutional contracts and payment structures. Secondary prophylaxis should focus on non-antimicrobial options to lessen the impact on the microbiome. The oral option of fecal microbiota transplantation (FMT), SER109, and the now FDA-approved RBX2660 represent exciting new options to correct dysbiosis. Bezlotoxumab is another attractive option to prevent recurrences. Further head-to-head studies of newer agents will be needed to guide selection of the optimal therapies for CDI primary and secondary prophylaxis.

The objective of this systematic review is to summarize in vitro, preclinical, and human data related to omadacycline and Clostridioides difficile infection (CDI).

PubMed and Google Scholar were searched for "omadacycline" AND ("Clostridium difficile" OR "C difficile" OR "Clostridioides difficile") for any studies published before February 15, 2022. The US Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) was searched for omadacycline (for reports including "C. difficile" or "CDI" or "gastrointestinal infection"). The publications list publicly available at Paratek Pharmaceuticals, Inc. Web site was reviewed.

Publications presenting primary data on omadacycline and C. difficile published in English were included.

Preclinical and clinical evidence was extracted from 14 studies. No case reports in indexed literature and no reports on FDA AERS were found. Omadacycline has potent in vitro activity against many C. difficile clinical strains and diverse ribotypes. In phase 3 studies, there were no reports of CDI in patients who received omadacycline for either community-acquired bacterial pneumonia or acute bacterial skin and skin structure infection.

Omadacycline should be considered a low-risk antibiotic regarding its propensity to cause CDI.

Reducing the burden of CDI on patients and the health care system should be a priority. Patients with appropriate indications who are at heightened risk of CDI may be suitable candidates for omadacycline therapy. In these patients, omadacycline may be preferable to antibiotics with a high CDI risk.

Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented.

The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18 years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to group A, two doses of RBX2660; group B, two doses of placebo; or group C, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2 days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8 weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24 months.

For the primary endpoint, treatment success at 8 weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95% CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group.

While the phase 2b PUNCH CD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8 weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase 3 clinical trial, PUNCH CD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults.

ClinicalTrials.gov: NCT02299570.

A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.

To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.

This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.

SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.

The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.

Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).

In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.

ClinicalTrials.gov identifier: NCT03183141.

The aim of this study was to investigate the differences of Clostridioides difficile infection (CDI) during the COVID-19 pandemic compared to the pre-COVID-19 era. CDI patients treated at the Clinic for Infectious Diseases, Clinical Center of Vojvodina, Serbia during 2017-2019 (n = 304) were compared with COVID-19/CDI patients treated in period September 2021-September 2022 (n = 387). Groups were compared by age, gender, comorbidities, previous medications, laboratory findings, and outcome within 30 days. In the CDI/COVID-19 group, we found: greater percentage of males 59.8% vs. 42.6% (p ≤ 0.001), older age 72.8 ± 9.4 vs. 65.6 ± 11.7 (p ≤ 0.001), higher Charlson comorbidity score (CCS) (3.06 ± 1.54 vs. 2.33 ± 1.34 (p ≤ 0.001), greater percentage of chronic renal failure (33.9% vs. 23.4% (p = 0.003), malignances (24.3% vs. 13.5% (p ≤ 0.001), chronic obstructive pulmonary disease (22.7% vs. 15.5% (p = 0.017), higher usage of macrolide (38.5% vs. 8.6% (p ≤ 0.001), greater percentage of patients with hypoalbuminemia ≤25 g/L (19.6% vs. 12.2% (p ≤ 0.001), lower percentage of patients with elevated creatinine (≥200 mmol/L) (31.5% vs. 43.8%) (p = 0.002), and greater percentage of lethal outcome 29.5% vs. 6.6% (p ≤ 0.001). In the prediction of lethal outcome multivariate regression analysis extracted as an independent predictor, only higher CRP values in the non-COVID-19 group and in the COVID-19 group: older age (p ≤ 0.001), CCS (p = 0.019) and CRP (p = 0.015). COVID-19 changes the disease course of CDI and should be taken into consideration when managing those patients.

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20−25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.

Clostridioides difficile infection (CDI) is associated with a large burden of morbidity and mortality worldwide. Previous studies have developed models for predicting recurrence and mortality following CDI, but no machine learning predictive models have been developed specifically using data from Japanese patients.

Using a database of records from acute care hospitals in Japan, we extracted records from January 2012 to September 2016 (plus a 60-day lookback window). A total of 19,159 patients were included. We used a machine learning approach, XGBoost, and compared it to a traditional unregularized logistic regression model. The first 80% of the dataset (by patient index date) was used to optimize model hyperparameters and train the final models, and evaluation was performed on the remaining 20%. We measured model performance by the area under the receiver operator curve and assessed feature importance using Shapley additive explanations.

Performance was similar between the machine learning approach and the classical logistic regression model. Logistic regression performed slightly better than XGBoost for predicting mortality.

XGBoost performed slightly better than logistic regression for predicting recurrence, but it was not competitive with existing published models. Despite this, a future machine learning-based application provided in a bedside setting at low cost might be a clinically useful tool.