Clostridium Difficile Research Articles

EP39 - Retrospective study of delays in reversal of loop ileostomy – reasons and outcomes during the COVID era

Abstract Aims Formation of loop ileostomy is common after anterior resection to reduce the sequele of an anastomosis leak.1-5 Delays to reversal of ileostomy is associated with complications. Methods Retrospective study between 1 July 2017 – 30 June 2023. Patients were included: >18 years old, loop ileostomy formed as part of anterior resection surgery (benign and malignant). Exclusion criteria: loop ileostomy performed during other colonic resections, patients with inflammatory bowel disease, defunctioning ileostomy for obstructions. Primary outcome measures included complications associated with delayed closure of loop ileostomy and readmissions after reversal surgery. Secondary measures included reasons for delay to surgery, complications prior to reversal surgery, and morbidity and mortality associated with it. Results 135 patients were included. 85.9% of patients experienced delays in reversal surgery. Those without delays in surgery had higher rate of stoma-related complications (p=0.002). Delays were due to a long waitlist (p<0.01) and adjuvant chemotherapy (p=0.598). There was no significant differences in the delays to surgery during COVID pandemic. Delays were associated with higher rate of wound infection (6.04%), post-operative ileus (12.07%), anastomotic leak (1.72%), and Clostridium difficile (C.diff) infection (3.45%). Handsewn end to end anastomosis was associated with a higher proportion of post-operative ileus compared to the stapled side to side anastomosis group. Conclusion Reversal of ileostomy within 6 months of index surgery after adjuvant therapy could potentially reduce post-operative complications, and alleviate the burden on our healthcare system in the long run. A stapled side to side anastomosis should also be considered.

Toxin inhibition: Examining tetracyclines, clindamycin, and linezolid.

The purpose of this review is to discuss the role of toxin inhibition in select infections and to provide recommendations for appropriate antimicrobial selection when toxin inhibition is indicated. For select organisms, specifically Clostridioides difficile, Staphylococcus aureus, and Streptococcus pyogenes, toxin production plays an integral role in overall disease pathogenesis and progression. Some expert recommendations include utilization of an antimicrobial with toxin inhibition properties as primary or adjunctive therapy for certain infections due to these organisms, but evolving data have made the choice of antitoxin agent less clear. Clindamycin has been the long-standing standard of care agent for toxin inhibition in necrotizing S. aureus and S. pyogenes infections, but linezolid shows promise as an alternative either in the setting of drug shortages or simply when clindamycin is not optimal, while tetracyclines require further study for this indication. The role for adjunctive toxin inhibition in C. difficile infection (CDI) is less defined, as current first-line therapies already have antitoxin properties. Toxin inhibition plays a key role in successful management of patients with infections due to toxin-producing organisms. Adjunctive therapy with a tetracycline could be considered in severe, fulminant CDI, but the associated benefit is variable. The benefit of antitoxin treatment for necrotizing S. aureus and S. pyogenes has been more consistently documented. Recent studies support linezolid as an alternative to clindamycin as an adjunctive S. aureus treatment or as monotherapy when appropriate.

Dysbiosis of the gut microbiota is associated with in-hospital mortality in patients with antibiotic-associated diarrhoea: A metagenomic analysis

BackgroundThe increasing incidence of antibiotic-associated diarrhoea (AAD) is a serious health care problem. Dysbiosis of the gut microbiota is suspected to play a role in the pathogenesis of AAD, but its impact on the clinical outcomes of patients remains unclear. MethodsBetween May and October 2022, 210 patients with AAD admitted to a university hospital and 100 healthy controls were recruited. DNA extraction from stool specimens and shotgun sequencing were performed. Machine learning was conducted to assess profiling at different taxonomic levels and to select variables for multivariable analyses. ResultsPatients were classified into two groups: Clostridioides difficile infection (CDI, n = 39) and non-CDI AAD (n = 171). The in-hospital mortality rate for the patients was 20.0%, but the presence of C. difficile in the gut microbiota was not associated with mortality. Machine learning showed that taxonomic profiling at the genus level best reflected patient prognosis. The in-hospital mortality of patients was associated with the relative abundance of specific gut microbial genera rather than alpha-diversity: each of the five genera correlated either positively (Enterococcus, Klebsiella, Corynebacterium, Pseudomonas, and Anaerofustis) or negatively (Bifidobacterium, Bacteroides, Streptococcus, Faecalibacterium, and Dorea). Genes for vancomycin resistance were significantly associated with in-hospital mortality in patients with AAD (adjusted hazard ratios, 2.45; 95% CI, 1.20–4.99). ConclusionThis study demonstrates the potential utility of metagenomic studies of the gut microbial community as a biomarker for prognosis prediction in AAD patients.

Postoperative ileus in obstetric and gynecological practice: a prospective solution to the problem

Proton pump inhibitors (PPIs) are the undisputed leaders in the treatment of acid-related diseases. In actual clinical practice, the use of PPIs has been growing exponentially in recent decades. For a long time, PPIs were considered completely safe drugs for both short-term and long-term use. However, modern clinical guidelines and reviews and meta-analyses of the current decade on the safety of PPI use note that when prescribing PPIs in large doses for a long period, the possibility of developing numerous side effects should be taken into account. We searched the PubMed and Scopus information databases for publications on the safety of PPI use, including sources up to 12/01/2023. The review addresses issues of drug interactions between PPIs and chemotherapeutic drugs, which should certainly be taken into account in real clinical practice. In addition, recent reviews and meta-analyses have examined side effects of long-term PPI use, such as increased risk of infection (Clostridium difficile infection, community-acquired pneumonia), electrolyte disturbances, kidney damage, increased risk of hip, wrist and spine fractures; increased cardiovascular risk and a number of others, which can also have an adverse effect on the prognosis of cancer patients. The risk of developing gastric cancer with long-term PPI therapy can be considered as a likely side effect, since their association with PPI use is not denied or questioned in recent reviews and meta-analyses. There is still uncertainty regarding the increased risk of other cancers, since there are publications that do not confirm their association with PPI use. However, the presented review, despite a number of contradictions, allows us to conclude that the increased cancer risk with long-term use of PPIs is real and must be taken into account when prescribing PPIs for a long term.

Pangenome analysis of Clostridium scindens : a collection of diverse bile acid and steroid metabolizing commensal gut bacterial strains.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids deoxycholic acid and lithocholic acid from the primary bile acids cholic acid and chenodeoxycholic acid, respectively, as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized in vitro and in vivo to any significant extent. The formation of secondary bile acids is important in maintaining normal gastrointestinal function, in regulating the structure of the gut microbiome, in the etiology of such diseases such as cancers of the GI tract, and in the prevention of Clostridium difficile infection. We therefore wanted to determine the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the 34 strains of C. scindens have an open pangenome with 12,720 orthologous gene groups, and a core genome with 1,630 gene families, in addition to 7,051 and 4,039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The core genome contains 39% of the proteins with predicted metabolic function, and, in the unique genome, the function of storage and processing of information prevails, with 34% of the proteins being in that category. The pangenome profile including the MAGs also proved to be open. The presence of bile acid inducible ( bai ) and steroid-17,20-desmolase ( des ) genes was identified among groups of strains. The analysis reveals that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, confirmed by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

Therapeutics involved in managing initial and recurrent Clostridium difficile infection: An updated literature review.

Clostridium difficile infection (CDI) has been increasing due to the effect of recurrent hospitalizations. The use of antibiotics has been shown to alter the gut microbiome and lead to CDIs. The treatment is limited to three major antibiotics; however, the incidence of recurrent CDIs has been increasing and drug resistance is a major concern. This aspect is a growing concern in modern medicine especially in the elderly population, critical care patients, and immunocompromised individuals who are at high risk of developing CDIs. Clostridium difficile can lead to various complications including septic shock and fulminant colitis that could prove to be lethal in these patients. Newer modalities of treatment have been developed including bezlotoxumab, a monoclonal antibody and fecal microbiota transplant. There have been studies showing asymptomatic carriers and drug resistance posing a major threat to the healthcare system. Newer treatment options are being studied to treat and prevent CDIs. This review will provide an insight into the current treatment modalities, prevention and newer modalities of treatment and challenges faced in the treatment of CDIs.

Diagnosis and management of Clostridioides difficile in inflammatory bowel disease.

Patients with IBD have an increased risk for Clostridioides difficile infection (CDI), which can lead to worse IBD outcomes. The diagnosis of CDI in IBD patients is complicated by higher C. difficile colonization rates and shared clinical symptoms of intestinal inflammation. Traditional risk factors for CDI, such as antibiotic exposure, may be lacking in IBD patients due to underlying intestinal microbiota dysbiosis. While CDI disproportionately affects people with IBD, patients with IBD are typically excluded from CDI clinical trials creating a knowledge gap in the diagnosis and management of these two diseases. This narrative review aims to provide a comprehensive overview of the diagnosis, treatment, and prevention of CDI in IBD patients. Distinguishing CDI from C. difficile colonization in the setting of an IBD exacerbation is important to avoid treatment delays. When CDI is diagnosed, extended courses of anti-C. difficile antibiotics may lead to better CDI outcomes. Regardless of a diagnosis of CDI, the presence of C. difficile in an IBD patient should prompt a disease assessment of the underlying IBD. Microbiota-based therapies and bezlotoxumab appear to be effective in preventing CDI recurrence in IBD patients. Patients with IBD should be considered high risk for CDI recurrence and evaluated for a preventative strategy when diagnosed with CDI. Ultimately, the co-management of CDI in an IBD patient requires a nuanced, patient-specific approach to distinguish CDI from C. difficile colonization, prevent CDI recurrence, and manage the underlying IBD.

Virulence factors, antibiotic susceptibility and sequence type distribution of hospital-associated Clostridioides difficile isolates in Israel, 2020–2022

Biofilm formation and toxin production are some of the virulence factors of Clostridioides difficile (C. difficile), which causes hospital-acquired C. difficile infection (HA-CDI). This work investigated the prevalence and distribution of different strains recovered from HA-CDI patients hospitalized in 4 medical centres across Israel, and characterized strains' virulence factors and antibiotic susceptibility. One-hundred and eighty-eight faecal samples were collected. C. difficile 's toxins were detected by the CerTest Clostridium difficile GDH + Toxin A + B combo card test kit. Toxin loci PaLoc and PaCdt were detected by whole-genome sequencing (WGS). Multi-locus sequence typing (MLST) was performed to classify strains. Biofilm production was assessed by crystal violet. Antibiotic susceptibility was determined using Etest. Fidaxomicin susceptibility was tested via agar dilution. Sequence type (ST) 42 was the most (13.8%) common strain. All strains harboured the 2 toxins genes; 6.9% had the binary toxin. Most isolates were susceptible to metronidazole (98.9%) and vancomycin (99.5%). Eleven (5.85%) isolates were fidaxomicin-resistant. Biofilm production capacity was associated with ST (p < 0.001). In conclusion, a broad variety of C. difficile strains circulate in Israel's medical centres. Further studies are needed to explore the differences and their contribution to HA-CDI epidemiology.

Gut microbial and metabolic features associated with Clostridioides difficile infection recurrence in children

Abstract Background Recurrent Clostridioides difficile (C. difficile) infection (rCDI) is a critical clinical issue due to the increase in incidence and difficulty in treatment. We aimed to identify gut microbial and metabolic features associated with disease recurrence in a group of pediatric CDI patients. Methods A total of 84 children with primary CDI were prospectively enrolled in the study. Fecal samples collected at the initial diagnosis were subjected to 16S rRNA gene sequencing and targeted metabolomics analysis to profile the bacterial composition and metabolome. Results Twenty-six (26/84, 31.0%) pediatric CDI patients experienced recurrence. The alpha diversity of the fecal microbiota was significantly lower in the recurrent group than in the nonrecurrent group, and the beta diversity was different from that of the nonrecurrent group. Taxonomic profiles revealed that the relative abundances of multiple bacterial taxa significantly differed between the recurrent and nonrecurrent groups. Linear discriminant analysis (LDA) effect size (LEfSe) analysis identified several bacterial genera that discriminated between recurrent and nonrecurrent groups, including Parabacteroides, Coprococcus, Disalister and Clostridium. Recurrent bacteria presented lower abundances of several short-chain fatty acid (SCFA)-producing bacteria (Faecalibacterium, Butyricicoccus, Clostridium, Roseburia, and Ruminococcus), which were correlated with reduced fecal SCFA levels. In addition, several bile acids (BAs), including lithochalic acid (LCA), 12-ketoLCA, trihydroxycholestanoic acid (3-DHCA), and deoxycholic acid (DCA), were decreased in recurrent patients. Conclusions Our study suggests that the differing gut microbiota profiles in pediatric CDI patients may contribute to disease recurrence by modulating SCFA concentrations and BA profiles. The gut microbiota and metabolite signatures may be used to predict disease recurrence in children with CDI.

Epidemiologic characteristics and risk factors of Clostridioides difficile infection in patients with active tuberculosis in the Republic of Korea: a nationwide population-based study

The relationship between anti-tuberculosis (TB) agents and Clostridioides difficile infection (CDI) remains unclear. This study aimed to investigate the epidemiological characteristics and risk factors for CDI in patients with TB. This nationwide, population-based cohort study was conducted in the Republic of Korea (ROK) between January 2018 and December 2022. Data were extracted from the National Health Insurance Service (NHIS) National Health Information Database. The risk factors for CDI in patients with TB were identified through multivariate logistic regression analysis using a 1:4 greedy matching method based on age and sex. During the study period, CDI developed in 2,901 of the 131,950 patients with TB who were prescribed anti-TB agents. The incidence of CDI in patients with TB has increased annually in the ROK from 12.31/1000 in 2018 to 33.51/1000 in 2022. Oral metronidazole (81.94%) was the most common first-line treatment for CDI. The in-hospital mortality rate of patients with concomitant CDI and tuberculosis was 9.9% compared with 6.9% in those with TB alone (P<0.0001). Multivariate logistic regression analysis found intensive care unit admission, Charlson Comorbidity Index ≥3, antibiotics exposure, standard regimen, multidrug resistant TB, and extrapulmonary TB as significant risk factors for development of CDI in patients with TB. CDI is uncommon in patients with TB, but it results in a significantly increased mortality rate. Patients being treated for TB should be carefully monitored for the development of CDI. Further clinical research is warranted to identify effective interventions for preventing and controlling CDI during TB treatment.

Outpatient use of antibiotics in uncomplicated diverticulitis decreases hospital admissions.

Recently, antibiotics use in uncomplicated acute diverticulitis (AD) has been controversial in Europe. The American Gastroenterological Association (AGA) in their 2015 guidelines recommend their selective use. Our study highlights their role in outpatient management. We queried the Diamond Network through TriNetX-Research Network including 92 healthcare organizations. We included large intestine diverticulitis without perforation, abscess or bleeding. Exclusion criteria included any of sepsis criteria, CRP > 15 mg/L, immunodeficiency or HIV, coronary artery disease, chronic kidney disease, history of Crohn's disease or ulcerative colitis, heart failure, hypertension, diabetes or any of the following in the 3 months before study date; clostridium difficile (C. diff) infection, diverticulitis or antibiotics. Patients with AD were divided into two cohorts; patients on antibiotics, and patients not on antibiotics. Cohorts were compared after propensity-score matching (PSM). 214,277 patients met inclusion criteria. 58.9% received antibiotics, and 41% did not. After PSM, both cohorts had 84,320. Rate of hospital admission was lower in the antibiotic group (3.3% vs 4.2%, p < .001). There was a statistical difference between ICU admission (0.1% vs 0.15%, p < .01) and the rate of bowel perforation, peritonitis, abscess formation or bleeding (1.3% vs 1.4%, p = .044). There was no difference in mortality (0.1% vs 0.1%, p = .11), C. diff (0.1% vs 0.1%, p = .9), colectomies (0.2% vs 0.2%, p = .33), or Acute Kidney Injury (AKI) (0.1% vs 0.1%, p = .28). Outpatient use of antibiotics in patients with uncomplicated AD is associated with lower rates of hospital admissions and complications without changing mortality rate or surgical intervention.

Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

Antibiotic Prophylaxis During Allogeneic Stem Cell transplantation—A Comprehensive Single Center Retrospective Analysis

BackgroundProphylactic antibiotics are still controversial during allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our transplant center, we suspended antibiotic prophylaxis during allo-HSCT in 2017. ObjectiveThe main objective of this study was the detailed analysis of the potentially beneficial impact of omittance of standard antibiotic prophylaxis during allo-HSCT in survival and Graft-versus-Host disease (GvHD) development, especially with consideration of confounding factors and competing events. Secondary objectives were the evaluation of the risk of severe infections and transplant-related mortality without antibiotic prophylaxis, the detailed assessment of bacterial and viral infections including multiresistant pathogens as well as occurrence of relapse in both groups. This study aims to support the development of future antibiotic strategies in allo-HSCT. Study DesignWe retrospectively analyzed patient outcome in the time periods before (between December 2012 and February 2017) and after suspension (between March 2017 and June 2020) of antibiotic prophylaxis during allo-HSCT. Relevant clinical outcome parameters of the patients (n = 221) were collected by chart-review in the two groups (with antibiotic prophylaxis n = 101 versus without antibiotic prophylaxis n = 120). All patients were 18 years or older. Propensity score methods were used to adjust for potentially confounding patient characteristics. To address competing events, transitions between moderate/severe acute and chronic GvHD, relapse and death were analyzed using an inverse-propensity score weighted multistate modeling approach. ResultsWhile we observed a trend towards an improved outcome in the cohort without antibiotic prophylaxis, the inverse-propensity-score-weighted analyses did not show significant differences between the two groups in overall survival (OS) (P = .811) or development of acute GvHD (aGvHD) grade 3/4 (P = .158) and chronic moderate/severe GvHD (cGvHD) (P = .686). Multistate analysis respecting competing events revealed comparable estimated probabilities without antibiotic prophylaxis versus with antibiotic prophylaxis in OS (35.0% [95% CI: 28.2%-42.7%] versus 35.3% [95% CI: 27.8%-41.1%]) as well as development of aGvHD grade 3/4 (7.7% [95% CI: 5.9%-12.2%] vs. 10.6% [95% CI: 7.7%-15.7%]) and moderate/severe cGvHD (21.0% [95% CI: 17.7%-30.0%] vs. 23.8% [95% CI: 19.6%-31.4%]). Similar analyses showed also no significant differences in relapse rate, transplant-related mortality, relapse-related mortality, or GvHD-free/relapse-free survival between the two groups. An observed increase in severe infections without antibiotic prophylaxis did not lead to a significantly higher mortality rate. Viral reactivation and detection of multiresistant bacteria were comparable, yet a higher incidence of Clostridioides difficile infections was observed in patients receiving antibiotic prophylaxis. ConclusionOur study supports previous reports of noninferiority of allo-HSCT without use of antibiotic prophylaxis with close monitoring and rapid intervention, if infection is suspected. The trend towards improved outcomes without antibiotic prophylaxis, however, might not only be due to the absence of antibiotic prophylaxis but also due to additional progresses in the field over the recent years. While the present study is too small to draw definite conclusions, these results strongly warrant further multicenter studies addressing the potential benefit of omitting antibiotic prophylaxis during allo-HSCT.

Fecal Microbiota, Live-jslm (RBL; REBYOTA ® ) for Prevention of Recurrent Clostridioides difficile Infection: What Gastroenterology Nurses Need to Know.

Live biotherapeutic products (LBPs) such as fecal microbiota, live-jslm (RBL) are becoming more frequently administered in gastroentintestinal (GI) care settings. As a result, GI nurses must be knowledgeable about and skilled in their administration of LBPs. RBL is a single-dose, rectally-administered, microbiota-based LBP suspension indicated for prevention of recurrent Clostridioides difficile infection (rCDI). RBL contains a diverse set of micro-organisms, including Bacteroides spp., and is believed to restore a healthy gut microbiota to mitigate dysbiosis associated with rCDI. Patients do not require fasting, bowel preparation, or anesthesia prior to RBL administration. Administration takes approximately 5minutes and can be given by any health care professional (e.g., nurses) in any care setting. Nurses also play an important role in educating patients and caregivers about these products and the disease. Collectively, improved familiarity with LBPs and their proper use among nurses can contribute to successful prevention of rCDI in their patients.

Preferences for a Clostridioides difficile vaccine among adults in the United States

IntroductionClostridioides difficile (C.diff) infection (CDI) causes significant morbidity and mortality among older adults. Vaccines to prevent CDI are in development; however, data on the target population's preferences are needed to inform vaccination recommendations in the United States (US). This study assessed US adults' willingness to receive a C.diff vaccine and examined how vaccine attributes influence their choices. MethodsA cross-sectional online survey with a discrete choice experiment (DCE) was conducted among US adults aged ≥50 years. DCE attributes included effectiveness, duration of protection, reduction in symptom severity, out-of-pocket (OOP) costs, number of doses, and side effects. The DCE included 11 choice tasks, each with two hypothetical vaccine profiles and an opt-out (i.e., no vaccine). Attribute-level preference weights were estimated using hierarchical Bayesian modeling. Attribute relative importance (RI) was compared between select subgroups. ResultsOf 1216 adults in the analyses, 29.9% reported they knew either ‘a little’ (20.7%) or ‘a lot’ (9.2%) about C.diff before the study. A C.diff vaccine was chosen 58.0% of the time (vs. opt-out) across choice tasks. It was estimated that up to 75.0% would choose a vaccine when OOP was $0. Those who were immunocompromised/high-risk for CDI (vs. not) more frequently chose a C.diff vaccine. Decreases in OOP costs (RI = 56.1), improvements in vaccine effectiveness (RI = 17.7), and reduction in symptom severity (RI = 10.3) were most important to vaccine choice. The rank ordering of attributes by importance was consistent across subgroups. ConclusionOOP cost, improvements in vaccine effectiveness, and reduction in CDI severity were highly influential to vaccine selection. Most adults aged ≥50 years were receptive to a C.diff vaccine, especially with little-to-no OOP cost, suggesting that mandating insurance coverage of vaccination with no copayment may increase uptake. The limited awareness about C.diff among adults presents an opportunity for healthcare providers to educate their patients about CDI prevention.

Clostridioides difficile Infections in Children: What Is the Optimal Laboratory Diagnostic Method?

The diagnosis of Clostridioides difficile infection (CDI) in the pediatric population is complicated by the high prevalence of asymptomatic colonization, particularly in infants. Many laboratory diagnostic methods are available, but there continues to be controversy over the optimal laboratory testing approach to diagnose CDI in children. We evaluated commonly used C. difficile diagnostic commercial tests in our pediatric hospital population at Sidra Medicine in Doha, Qatar. Between June and December 2023, 374 consecutive stool samples from pediatric patients aged 0-18 years old were tested using: Techlab C. diff Quik Chek Complete, Cepheid GeneXpert C. difficile, QIAstat-Dx Gastrointestinal Panel, and culture using CHROMagar C. difficile. The results of these tests as standalone methods or in four different testing algorithms were compared to a composite reference method on the basis of turnaround time, ease of use, cost, and performance characteristics including specificity, sensitivity, negative predictive value, and positive predictive value. Our study showed variability in test performance of the different available assays in diagnosing CDI. In our population, a testing algorithm starting with Cepheid GeneXpert C. difficile PCR assay or QIAstat-Dx Gastrointestinal panel as a screening test followed by toxin immunoassay for positive samples using the Techlab C. diff Quik Chek Complete kit showed the best performance (100% specificity and 100% positive predictive value) when combined with clinical review of the patient to assess risk factors for CDI, clinical presentation, and alternative causes of diarrhea.

Prevention and cure of murine C. difficile infection by a Lachnospiraceae strain

ABSTRACT We sought to better understand how intestinal microbiota confer protection against Clostridioides difficile (C. difficile) infection (CDI). We utilized gnotobiotic altered Schaedler flora (ASF) mice, which lack the abnormalities of germfree (GF) mice as well as the complexity and heterogeneity of antibiotic-treated mice. Like GF mice, ASF mice were highly prone to rapid lethal CDI, without antibiotics, while very low infectious doses resulted in chronic CDI. Administering such chronic CDI mice an undefined preparation of Clostridia lowered C. difficile levels by several logs. Importantly, such resolution of CDI was associated with colonization of Lachnospiraceae. Fractionation of the Clostridia population to enrich for Lachnospiraceae led to the appreciation that its CDI-impeding property strongly associated with a specific Lachnospiraceae strain, namely uncultured bacteria and archaea (UBA) 3401. UBA3401 was recalcitrant to being propagated as a pure culture but could be maintained in ASF mice, wherein it comprised up to about 50% of the intestinal microbiota, which was sufficient to generate a high-quality genomic sequence of this bacterium. Sequence analysis and ex vivo study of UBA3401 indicated that it had the ability to secrete substance(s) that directly impeded C. difficile growth. Moreover, in vivo administration of UBA3401/ASF feces provided strong protection to C. difficile challenge. Thus, UBA3401 may contribute to and/or provide a means to study microbiota-mediated CDI resistance.

Gut microbiome and plasma lipidome analysis reveals a specific impact of Clostridioides difficile infection on intestinal bacterial communities and sterol metabolism.

There is increasing evidence about the influence the changes in microbiota and its metabolism has on numerous diseases and infections such as Clostridioides difficile infection (CDI). The knowledge of these changes at local and systemic levels can help us manage this infection to avoid recurrences and apply the best therapies, such as fecal microbiota transfer (FMT). This study shows a better restoration of the gut in FMT-treated patients than in antibiotic-treated patients, resembling healthy controls and showing increased levels of cholesterol-reducing bacteria. Furthermore, it evidences the CDI impact on plasma lipidome. We observed in CDI patients a global depletion in circulating lipids, particularly cholesteryl esters, and a specific decrease in linoleic acid-containing lipids, an essential fatty acid. Our observations could impact CDI management because the lipid content was only partially recovered after treatment, suggesting that continued nutritional support, aiming to restore healthy lipid levels, could be essential for a full recovery.

Contrasting methods to operationalize antibiotic exposure in clinical research: a real-world application on healthcare-associated Clostridioides difficile infection.

The goal of this article is to summarize common methods of antibiotic operationalization used in clinical research and demonstrate methods for exposure variable selection. We demonstrate three methods for modeling exposure, using data from a case-control study on Clostridioides difficile infection in hospitalized patients: 1) factor analysis, 2) logistic regression models, and 3) Least Absolute Shrinkage and Selection Operator (LASSO) regression. The factor analysis identified 8 variables contributing the most variation in the dataset: any antibiotic exposure; number of antibiotic classes; number of antibiotic courses; dose; and specific classes monobactam, 𝛽-lactam 𝛽-lactamase inhibitors, rifamycin, and cephalosporin. The logistic regression models resulting in the best model fit used predictors representing any antibiotic exposure and the proportion of a patient's hospitalization on antibiotics. The LASSO model selected 22 variables for inclusion in the predictive model, of which 10 were antibiotic exposure variables, including: any antibiotic exposure; classes 𝛽-lactam 𝛽-lactamase inhibitors, carbapenem, cephalosporin, fluoroquinolone, monobactam, rifamycin, sulfonamides, and miscellaneous; and proportion of hospitalization on antibiotics. Investigators studying antibiotic use should consider multiple characteristics of exposure informed by their research question and the theory on how antibiotics may impact the distribution of the outcome in their target population.

CLOVER: A Phase 3 Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N=17,535) to receive 3 PF-06425090 or placebo doses (0,1,6-months). Primary endpoints were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary endpoints), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability/safety was assessed. The primary endpoint was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE)=31.0% (96.4%CI: -38.7%-66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE=28.6% (-28.4%-61.0%)]). Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P=0.02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE=100% [95%CI: 59.6%-100.0%]) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE=100% [54.8%-100.0%]). Local reactions were more frequent in PF-06425090 recipients and systemic events were generally similar between groups; most were mild-to-moderate. AE rates were similar between groups. Three PF-06425090 doses were safe and well-tolerated. Although the primary endpoint was not met, PF-06425090 reduced symptom duration, CDI requiring medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. NCT03090191.