C. Difficile Infection Patients Research Articles

Molecular and Epidemiological Characterization of Pediatric and Adult C. difficile Infection in Canadian Hospitals, 2015-2022

Background: The molecular and epidemiological landscape of C. difficile infection (CDI) has evolved markedly in the last decade; however, limited information is available contrasting differences between adult and pediatric populations. We describe a multicenter study evaluating healthcare-associated (HA) and community-associated (CA) adult and pediatric-CDI identified in the Canadian Nosocomial Infection Surveillance Program (CNISP) network from 2015 to 2022. Methods: Hospitalized patients with CDI were identified from up to 84 hospitals between 2015–2022 using standardized case definitions. Cases were confirmed by PCR, cultured, and further characterized using ribotyping and E-test. We used two-tailed tests for significance (p≤0.05). Results: Of 30,817 cases reported, 29,245 were adult cases [HA-CDI (73.2%), CA-CDI (26.8%)] and 1,572 were pediatric cases [HA-CDI (77.7%), CA-CDI (22.3%)]. From 2015 to 2022, HA-CDI rates decreased 19.7% (p=0.007) and 29.4% (p=0.004) in adult and pediatric populations, respectively (Figure 1). CA-CDI rates remained relatively stable in the adult population (p=0.797), while decreasing 60.7% in the pediatric population (p=0.013). Median ages of adult and pediatric patients were 70 (interquartile range (IQR), 58–80) and seven (IQR, 3–13) years, respectively. Thirty-day all-cause mortality was significantly higher among adult vs. Pediatric CDI patients (11.0% vs 1.4%, p < 0.0001). No significant differences in other severe outcomes were found. Ribotyping and susceptibility data were available for 4,620 samples: 3,558 adult (77.0%) and 1,062 pediatric (23.0%). The predominant adult and pediatric ribotypes (RT) were 106 (12.2/16.2%), 027 (11.4/3.2%), and 014 (8.8/8.2%). Overall, RT027 prevalence significantly decreased from 17.9% in 2015 to 3.2% in 2022 (p=0.003), while RT106 increased from 8.5% to 14.4%. Resistance rates among adult and pediatric isolates were similar for all antimicrobials tested except moxifloxacin (16.2% vs. 6.2%, p < 0.0001, respectively). Adult moxifloxacin resistance decreased from 30% to 6.3% from 2015 to 2022 (p=0.006). Adults with moxifloxacin-resistant CDI were older (median: 74 vs. 69 years, p < 0.001) and had higher thirty-day all-cause mortality (13% vs. 9.8%, p=0.041) and recurrence (10% vs. 5.7%, p < 0.001) compared to those with moxifloxacin non-resistant CDI, while these trends were not observed in pediatric patients. Among RT027 strains, moxifloxacin resistance decreased from 91.0% in 2015 to 7.1% in 2022. There was one metronidazole-resistant pediatric sample in 2018 and no resistance to vancomycin or tigecycline in either population. Conclusion: We have found differences in the epidemiological and molecular characteristics of adult and pediatric CDI, with higher thirty-day all-cause mortality among adults. Overall, RT106 has replaced RT027 as the predominant ribotype with a concomitant decrease in fluoroquinolone resistance.

Fungal and bacterial gut microbiota differ between Clostridioides difficile colonization and infection.

Aim: The bacterial microbiota is well-recognized for its role in Clostridioides difficile colonization and infection, while fungi and yeasts remain understudied. The aim of this study was to analyze the predictive value of the mycobiota and its interactions with the bacterial microbiota in light of C. difficile colonization and infection. Methods: The mycobiota was profiled by ITS2 sequencing of fecal DNA from C. difficile infection (CDI) patients (n = 29), asymptomatically C. difficile colonization (CDC) patients (n = 38), and hospitalized controls with C. difficile negative stool culture (controls; n = 38). Previously published 16S rRNA gene sequencing data of the same cohort were used additionally for machine learning and fungal-bacterial network analysis. Results: CDI patients were characterized by a significantly higher abundance of Candida spp. (MD 0.270 ± 0.089, P = 0.002) and Candida albicans (MD 0.165 ± 0.082, P = 0.023) compared to controls. Additionally, they were deprived of Aspergillus spp. (MD -0.067 ± 0.026, P = 0.000) and Penicillium spp. (MD -0.118 ± 0.043, P = 0.000) compared to CDC patients. Network analysis revealed a positive association between several fungi and bacteria in CDI and CDC, although the analysis did not reveal a direct association between Clostridioides spp. and fungi. Furthermore, the microbiota machine learning model outperformed the models based on the mycobiota and the joint microbiota-mycobiota model. The microbiota classifier successfully distinguished CDI from CDC [Area Under the Receiver Operating Characteristic (AUROC) = 0.884] and CDI from controls (AUROC = 0.905). Blautia and Bifidobacterium were marker genera associated with CDC patients and controls. Conclusion: The gut mycobiota differs between CDI, CDC, and controls and may affect Clostridioides spp. through indirect interactions. The mycobiota data alone could not successfully discriminate CDC from controls or CDI patients and did not have additional predictive value to the bacterial microbiota data. The identification of bacterial marker genera associated with CDC and controls warrants further investigation.

688. Risk of Clostridioides difficile Infection and Antibiotic Associated Diarrhea in Patients Receiving Outpatient Parenteral Antimicrobial Therapy

Abstract Background The colonic microbiome plays a critical role in resisting the ingrowth of pathogenic microbes like Clostridioides difficile (C. difficile). Disruption of the microbiome by antibiotics is known to cause antibiotic-associated diarrhea (AAD) and C. difficile infection (CDI). Outpatient parenteral antimicrobial therapy (OPAT) reduces hospital length of stay and exposure to healthcare-associated pathogens which may decrease the incidence of CDI. Previous studies that compared patients who received metronidazole for non-CDI indications with those who did not found a reduction in CDI among patients who received metronidazole. The aim was to study the incidence of AAD and CDI in the OPAT patient population and compare the incidence rate between patients who received oral metronidazole for non-CDI indications with those who did not. Methods We retrospectively reviewed a cohort from our facility's OPAT program. We included adult patients (18 years or older) discharged to home or skilled nursing facility (SNF) on OPAT over a 2-year time span, regardless of diagnosis. Pregnant patients, patients with active CDI before starting OPAT, and those who were receiving an associated CDI treatment were excluded. Antibiotic-associated diarrhea was defined as 3 or more loose or watery stools per day with negative CDI testing or spontaneous improvement after stopping antibiotics. Community-onset and healthcare facility–associated CDI (CO-HCFA CDI) was defined as 3 or more watery stools per day with a positive stool C. difficile diagnostic test in the community or within the first 3 days of readmission, provided the diagnosis was made less than 4 weeks since discharge from a healthcare facility. Demographics of Patients Discharged on OPAT. Patients selected between June 1, 2018 and June 2020, grouped by whether or not they developed Clostridioides difficile infection (CDI). SD= standard deviation; Q1= 1st quartile; Q3= 3rd quartile. Results Of the 617 charts that met inclusion criteria, 31 had AAD and 3 had CO-HCFA CDI. Incidence of CO-HCFA CDI was < 1%; < 1 per 1000 person-day and incidence of AAD was 5.02%. The protective role of metronidazole could not be studied due to the rarity of CDI in this study. Patients with positive CDI after initiation of OPAT and associated characteristics. Conclusion Although our study was not able to answer our initial question when comparing the effect of metronidazole within OPAT groups and rates of CDI, our data is promising for showing low rates of CDI in patients receiving OPAT. This study demonstrates the putative benefits of OPAT with reduced CDI incidence regardless of use of anti-CDI drugs. Disclosures Tirdad Zangeneh, DO, AiCuris: Grant/Research Support

Multi-omics analysis of hospital-acquired diarrhoeal patients reveals biomarkers of enterococcal proliferation and Clostridioides difficile infection

Hospital-acquired diarrhoea (HAD) is common, and often associated with gut microbiota and metabolome dysbiosis following antibiotic administration. Clostridioides difficile is the most significant antibiotic-associated diarrhoeal (AAD) pathogen, but less is known about the microbiota and metabolome associated with AAD and C. difficile infection (CDI) with contrasting antibiotic treatment. We characterised faecal microbiota and metabolome for 169 HAD patients (33 with CDI and 133 non-CDI) to determine dysbiosis biomarkers and gain insights into metabolic strategies C. difficile might use for gut colonisation. The specimen microbial community was analysed using 16 S rRNA gene amplicon sequencing, coupled with untargeted metabolite profiling using gas chromatography-mass spectrometry (GC-MS), and short-chain fatty acid (SCFA) profiling using GC-MS. AAD and CDI patients were associated with a spectrum of dysbiosis reflecting non-antibiotic, short-term, and extended-antibiotic treatment. Notably, extended antibiotic treatment was associated with enterococcal proliferation (mostly vancomycin-resistant Enterococcus faecium) coupled with putative biomarkers of enterococcal tyrosine decarboxylation. We also uncovered unrecognised metabolome dynamics associated with concomitant enterococcal proliferation and CDI, including biomarkers of Stickland fermentation and amino acid competition that could distinguish CDI from non–CDI patients. Here we show, candidate metabolic biomarkers for diagnostic development with possible implications for CDI and vancomycin-resistant enterococci (VRE) treatment.

Gut Microbiota Associated with Clostridioides difficile Carriage in Three Clinical Groups (Inflammatory Bowel Disease, C. difficile Infection and Healthcare Workers) in Hospital Field.

Clostridioides difficile is an anaerobic spore-forming Gram-positive bacterium. C. difficile carriage and 16S rDNA profiling were studied in three clinical groups at three different sampling times: inflammatory bowel disease (IBD) patients, C. difficile infection (CDI) patients and healthcare workers (HCWs). Diversity analysis was realized in the three clinical groups, the positive and negative C. difficile carriage groups and the three analysis periods. Concerning the three clinical groups, β-diversity tests showed significant differences between them, especially between the HCW group and IBD group and between IBD patients and CDI patients. The Simpson index (evenness) showed a significant difference between two clinical groups (HCWs and IBD). Several genera were significantly different in the IBD patient group (Sutterella, Agathobacter) and in the CDI patient group (Enterococcus, Clostridioides). Concerning the positive and negative C. difficile carriage groups, β-diversity tests showed significant differences. Shannon, Simpson and InvSimpson indexes showed significant differences between the two groups. Several genera had significantly different relative prevalences in the negative group (Agathobacter, Sutterella, Anaerostipes, Oscillospira) and the positive group (Enterococcus, Enterobacteriaceae_ge and Enterobacterales_ge). A microbiota footprint was detected in C. difficile-positive carriers. More experiments are needed to test this microbiota footprint to see its impact on C. difficile infection.

Mucosal-associated invariant T (MAIT) cells from Clostridioides difficile-infected patients exhibit a distinct proinflammatory phenotype and enhanced cytotoxic activity.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells mainly found in the mucosa and peripheral blood. We have recently demonstrated that Clostridioides difficile activates MAIT cell in vitro. However, their role in the pathogenesis of C. difficile infection (CDI) in human patients remains elusive to date. In this study, we performed comprehensive immunophenotyping of MAIT cells derived from CDI patients and compared their phenotype to that of patients with inflammatory bowel diseases (IBD). Our study revealed that blood MAIT cells from CDI patients exhibit an interleukin 17a (IL-17a)-dominated proinflammatory phenotype and an increased readiness to synthesize the proinflammatory cytokine interferon γ (IFN-γ) following in vitro re-stimulation. Moreover, the cytotoxic activity of MAIT cells, as measured by surface CD107a and intracellular granzyme B expression, was strongly increased in CDI. Multi epitope ligand cartography (MELC) analysis of intestinal biopsies from CDI patients revealed that MAIT cells exhibit an increased production of granzyme B and increased cytotoxicity compared to the control group. Together with previously published in vitro data from our group, our findings suggest that MAIT cells are functionally involved in the immune response against C. difficile and contribute to the pathogenesis of CDI.

Diarrheal-associated gut dysbiosis in cancer and inflammatory bowel disease patients is exacerbated by Clostridioides difficile infection.

Low diversity gut dysbiosis can take different forms depending on the disease context. In this study, we used shotgun metagenomic sequencing and gas chromatography-mass spectrometry (GC-MS) to compared the metagenomic and metabolomic profiles of Clostridioides (Clostridium) difficile diarrheal cancer and inflammatory bowel disease (IBD) patients and defined the additive effect of C. difficile infection (CDI) on intestinal dysbiosis. The study cohort consisted of 138 case-mix cancer patients, 43 IBD patients, and 45 healthy control individuals. Thirty-three patients were also infected with C. difficile. In the control group, three well-known enterotypes were identified, while the other groups presented with an additional Escherichia-driven enterotype. Bacterial diversity was significantly lower in all groups than in healthy controls, while the highest level of bacterial species richness was observed in cancer patients. Fifty-six bacterial species had abundance levels that differentiated diarrheal patient groups from the control group. Of these species, 52 and 4 (Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae, and Ruminococcus gnavus) were under-represented and over-represented, respectively, in all diarrheal patient groups. The relative abundances of propionate and butyrate were significantly lower in fecal samples from IBD and CDI patients than in control samples. Isobutyrate, propanate, and butyrate concentrations were lower in cancer, IBD, and CDI samples, respectively. Glycine and valine amino acids were over- represented in diarrheal patients. Our data indicate that different external and internal factors drive comparable profiles of low diversity dysbiosis. While diarrheal-related low diversity dysbiosis may be a consequence of systemic cancer therapy, a similar phenotype is observed in cases of moderate to severe IBD, and in both cases, dysbiosis is exacerbated by incidence of CDI.

Antibiotics Associated With Clostridium difficile Infection.

Introduction Clostridium difficile (C. difficile) is one of the major causes of diarrheatransmitted by the fecal-oral route. C. difficiletype BI/NAP1/027is responsible for the most severe C. difficile infection (CDI). It is a major cause of antibiotic-associated diarrhea followed byClostridium perfringens,Staphylococcus aureus,andKlebsiella oxytoca. Historically, clindamycin, cephalosporins, penicillins, and fluoroquinolones were related to CDI. We conducted this study to evaluate the antibiotics associatedwith CDI in recent times. Methods We conducted a retrospective, single-center study over a period of eight years. A total of 58 patients were enrolled in the study. Patients withdiarrhea and positive C. difficile toxin in stool were evaluated for antibiotics given, age, presence of malignancy,previous hospital stay for more than three days in the last three months, and any comorbidities. Results Among patients who developed CDI, prior antibiotics for at least four days duration were given in 93% (54/58) of patients. The most common antibiotics associated with C. difficile infection were piperacillin/tazobactam in 77.60% (45/58), meropenem in 27.60% (16/58), vancomycin in 20.70% (12/58), ciprofloxacin in 17.20% (10/58), ceftriaxone in 16% (9/58), and levofloxacin in 14% (8/58) of patients, respectively. Seven percent (7%) of patients with CDI did not receive any prior antibiotics. Solid organ malignancy was present in67.20% and hematological malignancy in 27.60% of CDI patients. Ninety-eight percent (98%, 57/58) of patients treated with proton pump inhibitors, 93% of patients with a previous hospital stay for more than three days,24% of patients with neutropenia, 20.1% of patients aged more than 65 years, 14% of patients with diabetes mellitus, and 12%of patients with chronic kidney disease also developed C. difficile infection. Conclusion The antibiotics associated with C. difficile infection are piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Other risk factors for CDI are proton pump inhibitor use, prior hospital admission, solid organ malignancy, neutropenia, diabetes mellitus (DM), and chronic kidney disease (CKD).

Clinical outcomes for Clostridioides difficile associated diarrhea in inflammatory bowel disease patients versus non-IBD population: A retrospective cohort study.

Patients with inflammatory bowel disease (IBD) have a higher incidence of Clostridioides difficile infection (CDI). Previous studies have demonstrated negative clinical outcomes in IBD patients with CDI compared to patients without CDI. The clinical presentation of CDI is indistinguishable from IBD exacerbation, thus posing a frequent clinical dilemma on the role of Clostridioides infection in the testing, diagnosis, and treatment of these patients. To compare clinical outcomes of CDI in patients with IBD to those without IBD. Retrospective cohort of adult patients admitted to Rabin Medical Center Israel between the years 2014 and 2020 with a concurrent diagnosis of IBD and CDI. Matching 1:2 was performed between the IBD patients and the non-IBD population with respect to age and sex. Sixty-seven patients with IBD and 134 patients without IBD were included in the study. The groups' median age was 40.6 (interquartile range [IQR] of 29.8-68.9), with 45.8% male and 54.2% female. The non-IBD group had a higher Charlson score with 2 (IQR 0; 5) versus 0 (IQR 0; 4) in the IBD group (P value <.01). Patients with IBD had more exposure to systemic antibiotics, 71.1% versus 26.3% (P value <.01). In a multivariable analysis we found no difference in 90-day mortality and rate of relapse between the 2 study groups with an odds ratio of 1.709 (95% confidence interval 0.321-9.905) and odds ratio of 0.209 (95% confidence interval 0.055-1.513) respectively. In our cohort patients with IBD who present with diarrhea and concomitant CDI have similar rates of relapse and mortality compared with patients without IBD.

Discovery of putative natural compounds inhibitor of the germinant spore receptor CspC in Clostridioides difficile infection: Gaining insights via In silico and bioinformatics approach

A Gram-positive anaerobic bacillus known as Clostridioides difficile (C. difficile) present in the intestinal tract of humans is the causative organism for C. difficile infection (CDI). A prospective target for the therapy of CDI is the germinant spore receptor CspC, a key regulator of the germination mechanism. The detection of bile acids by CspC has been reported to initiate the germination and signaling pathways in CDI. Herein, we examined small molecule compounds with putative inhibitory efficacies on CspC using integrative computational modeling approach. Due to their higher binding affinities as compared to metronidazole (Reference drug), the computational analysis identified three compounds (Hesperetin, Galbanic acid, and Tomatidine) as potential therapeutics for the receptor target. At the end of the 100ns molecular dynamics simulation, the stability investigations revealed Tomatidine and Galbanic acid to be more stable compounds compared to other simulated natural compounds, including the reference drug (Metronidazole). They also exhibited acceptable drug-likeness and pharmacokinetic properties as determined by the Lipinski’s rule of five. Notwithstanding the results of our study, it is still too premature to conclude that the drug candidates are appropriate for use among CDI patients without substantial clinical and preclinical research.

Microbial ecology between Clostridioides difficile and gut microbiota.

Clostridioides difficile colonizes a polymicrobial environment in the intestine and is a causative agent for antibiotic-associated diarrhea (AAD) and pseudomembranous colitis (PMC). The most important virulence factors of C. difficile are bacterial toxins, and three toxins (toxin A, toxin B, and binary toxin) are produced by toxigenic strains. Other virulence factors include spores, flagella, capsules, biofilms, hydrolytic enzymes and adhesins. C. difficile infection (CDI) is specifically diagnosed by anaerobic culture and toxin detection by either nucleic acid amplification test (NAAT) or enzyme-linked immunosorbent assay (ELISA). For treatment of CDI, metronidazole, vancomycin and fidaxomicin are used based on the severity of CDI. Mutual interaction between C. difficile and gut microbiota is associated with pathogenesis of CDI, and decreased microbial diversity with altered gut microbiome was detected in CDI patients. Restoration of certain gut microbiota is considered to be potentially effective for the prevention and treatment of CDI, and an ideal goal for CDI patients is restoration of the gut microbiota to a healthy state. Fecal microbiota transplantation (FMT) is a highly successful method of microbiome restoration and has been reported to be effective for the prevention of recurrent CDI. In addition, approaches to restoring the gut microbiota by using probioitcs and live biotherapeutic products (LBPs) are currently being studied to examine the effect on CDI. Further microbial ecological research on C. difficile and gut microbiota could lead to a better understanding of the pathogenesis and treatment of CDI.

A Cross-Sectional Study of Clostridium Difficile Infection in Inpatients with Antibiotic Associated Diarrhea.

Clostridium difficile (C. difficile) is a Gram-positive, anaerobic, spore-forming bacillus that can cause pseudomembranous colitis and other C. difficile-associated diseases, resulting in significant morbidity and mortality. The incidence and clinical features vary by geography. In this cross-sectional study, we examined the incidence and clinical features of C. difficile infection (CDI) within a 2,900-bed academic medical center in a southern area of China from January 1, 2017, to December 31, 2020. All adult inpatients (aged ≥ 18 years) who submitted loose stool samples for C. difficile testing over this period were considered for the study. This cross-sectional study showed that the average incidence of CDI was 2.07 cases/100,000 hospital patient-days. The mean age of these inpatients was 71.21 ± 2.83 years (range 30 - 93 years), and 83.61% (51/61) were treated in medical units. We found that 85.25% (52/61) of inpatients with CDI were aged > 60 years. Multivariate logistic regression analysis revealed that age > 60 years, and admission to the geriatric treatment unit or neurosurgery treatment unit were indeed independent risk factors for CDI in inpatients. The incidence of CDI in the southern area of China was low. Age > 60 years, and treatment in geriatric or neurosurgery units were independent risk factors for CDI inpatients.

Razvoj i implementacija protokola za prevenciju Clostridioides difficile infekcija usmerenog na poboljšanje sestrinskih veština

Introduction: Hospitalized patients have an increased risk of developing infections caused by Clostridioides difficile. Due to the changing epidemiology of C. difficile, it is necessary to educate nurses about the implementation of prevention measures, but also about the criteria for obtaining a quality sample of feces in order to establish an etiological diagnosis in a timely manner. The aim of the study was to assess gaps and flaws in C. difficile infection (CDI) prevention policies and practices, and to determine whether a nurses knowledge about early identification and isolation of CDI patients improved after education. Methods: The research was conducted in a quasi-experimental study at the University Clinical Center of the Republka Srpska (UKC RS) in the period from May 2020 to December 2021 on a sample of 60 nurses. A survey questionnaire Centers for Disease Control and Prevention (CDC) was used as a research instrument and it was intended for the assessment of knowledge, attitudes and understanding about procedures for the prevention of infection with C. difficile. The applied strategy to prevent hospital CDI was based on the introduction of the concept of "package of care", which was based on scientific evidence. For the education of nurses, interactive educational modules were used that contained detailed prevention measures CDI in hospital conditions in accordance with the guidelines. Before and after the education, the participants completed a knowledge test about C. difficile and prevention CDI.The study was approved by the Ethics Committee of the UKC RS. Results: Only 5 (8.3%) respondents stated that they were informed about CDI prevention during the visit of a nurse from the infection control team. Most of the shortcomings during the assessment of CDI prevention at the observed clinics were related to the practice of sending feces samples for laboratory testing for C. difficile. Nurses showed highly statistically significant (p&lt;0.001) better knowledge about the importance of early identification of C. difficile and isolation of CDI patients in the post-education test. Conclusions: The implementation of a CDI prevention protocol intended for nurses can be one of the algorithms that will precisely identify C. difficile, and thus successfully implement CDI prevention measures.

Melatonin as an Antimicrobial Adjuvant and Anti-Inflammatory for the Management of Recurrent Clostridioides difficile Infection.

Background:Clostridioides difficile (C. difficile) infection (CDI) is strongly associated with inflammation and has the potential to cause recurrent infections. Pre-clinical data suggest that melatonin has beneficial effects in the gastrointestinal tract due to its anti-inflammatory and antibacterial properties. This analysis examines the association between melatonin and the risk of recurrent CDI. Methods: A retrospective cohort study was conducted among patients with an inpatient diagnosis of CDI along with a positive C. difficile polymerase chain reaction (PCR) or enzyme immunoassay (EIA) test result. Patients were followed until the first study end point (death) or the first instance of recurrent infection. Propensity-score weighting was utilized accounting for confounding factors and weighted Cox models were estimated. Results: A total of 24,782 patients met the inclusion criteria, consisting of 3457 patients exposed to melatonin and 21,325 patients with no melatonin exposure. The results demonstrate that those exposed to melatonin were associated with a 21.6% lower risk of recurrent CDI compared to patients without melatonin exposure (HR = 0.784; 95% CI = 0.674-0.912). Conclusion: Our results demonstrate a decreased rate of recurrent CDI in patients exposed to melatonin. Further research on melatonin as an antimicrobial adjuvant and anti-inflammatory is warranted for the management of recurrent CDI.

Outcomes of Patients Who Developed Clostridioides difficile Infection During Hospitalization and Had a History of Comorbid Post-Traumatic Stress Disorder.

Introduction: Clostridioides difficile (C. difficile), is a common cause of nosocomial diarrhea. Antibiotic use is a risk factor for developing C. difficile infection (CDI). Clinical presentations of CDI range from mild diarrhea to fulminant colitis. A history of anxiety increases the risk of developing irritable bowel syndrome following CDI. Post-traumatic stress disorder (PTSD) is a common form of anxiety and is associated with several medical comorbidities. This study explores the impact PTSD has on the outcomes of adult patients who develop CDI while hospitalized.Methods: Hospitalized adults who had developed CDI were selected from the 2014 National Inpatient Sample database using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. The outcomes of CDI patients with and without comorbid PTSD were explored. The outcomes assessed in this study were inpatient mortality, sepsis, hypotension/shock, acute renal failure, acute respiratory failure, megacolon, colonic perforation, and intestinal abscess. Independent t-tests and chi-squared tests were used to compare means and proportions, respectively. A multivariate logistic regression analysis was utilized to determine whether PTSD is an independent predictor of the outcomes.Results: Among 72,383 hospitalized adults who developed CDI in the year 2014, 465 also had a diagnosis of PTSD. PTSD was found to be an independent risk factor for inpatient mortality (adjusted odds ratio {aOR} 2.93, 95% confidence interval (CI): 1.39-6.21, p = 0.005), and sepsis (aOR 1.61, 95% CI: 1.24-2.07, p = 0.001). However, PTSD was not a risk factor for hypotension/shock (aOR 1.26, 95% CI: 0.97-1.63, p = 0.080), acute renal failure (aOR 1.02, 95% CI: 0.81-1.28, p = 0.895), or acute respiratory failure (aOR 1.15, 95% CI: 0.83-1.58, p = 0.412) in patients with CDI. Due to small sample sizes of patients who developed megacolon, colonic perforation, and intestinal abscess, further analysis of these outcomes was not performed.Conclusion: Inpatients who develop CDI with comorbid PTSD are at increased risk for sepsis and inpatient mortality. These findings may be due to the impact of PTSD’s dysregulation of the hypothalamic-pituitary axis leading to low cortisol production, increased serum cytokine concentrations, and/or increased intestinal inflammation. Awareness of these increased risks when triaging CDI patients with PTSD and possibly increased psychiatric interventions to treat PTSD may be necessary to help reduce the risk of sepsis and inpatient mortality in this subgroup of patients.

Transmission Patterns of Clostridioides difficile in a Non-Epidemic Setting Based on WGS Analysis

Clostridioides difficile is a major nosocomial pathogen and has a considerable burden on healthcare systems. Our objective was to determine the transmission patterns of C. difficile in a non-epidemic setting using whole-genome multi-locus sequence typing (wgMLST) and core-genome single-nucleotide polymorphism (cgSNP) analyses. A retrospective study was conducted in a 650-bed university hospital between January 2016 and February 2017. In total, 191 strains isolated from 169 symptomatic C. difficile infection (CDI) patients were analyzed by WGS. Sequences were compared using wgMLST and cgSNP analyses. Genetic data and ward movements were then combined to identify the transmission rate and the type of transmission. The transmission rate varied from 55/169 (19.5%) (wgMLST) to 33/169 (32.5%) (cgSNP). Most transmission was considered cryptic, irrespective of the genetic analysis (38/55 [69.1%] by wgMLST to 25/33 [75.8%] by cgSNP). No transmission within the same ward was observed. In a non-epidemic setting, most C. difficile transmission occurs from sources other than symptomatic CDI patients.

The novel adjuvant, ADA-1, restores age-associated defects in the adaptive immune response to Clostridioides difficile infection and vaccination in an aging mouse model

Abstract Clostridioides difficile is the leading cause of healthcare-associated infection in the United States. The elderly (≥65) have the greatest risk of C. difficile infection (CDI), severe morbidity, and mortality due to CDI. Though antibody responses against C. difficile Toxin A/B (TcdA/B) following primary infection or vaccination are protective against symptomatic disease, the elderly have impaired humoral responses. Using an aging mouse model, we show that there is significantly greater morbidity and mortality in aged mice during primary CDI compared to young adult mice, as seen in elderly CDI patients. Additionally, during both primary CDI and vaccination against TcdA/B, aged mice have significantly lower anti-TcdA/B antibody titers. This impaired humoral response is the result of poor Tfh and B cell responses following infection and vaccination as aged mice have a significantly lower frequency of Tfh cells and number of anti-TcdA/B B cells compared to young adult mice. While these age-associated defects in the humoral response allow for increased vulnerability to CDI, we show that these defects can be restored with the addition of the novel adjuvant ADA-1 during vaccination of aged mice with TcdA/B-encoding DNA. With ADA-1, the anti-TcdA/B antibody response in aged mice is restored to levels seen in young adult mice. ADA-1 also boosts the frequency of Tfh cells in aged mice following vaccination, suggesting that ADA-1 can restore the development of the aged germinal center reaction following vaccination. As such, this work highlights both the need for the development of a C. difficile vaccine with the elderly in mind and presents ADA-1 as a solution to overcoming age-associated defects in the vaccine response of the elderly. Supported by Department of Defense Grant: W81XWH0910382 Pennsylvania Department of Health CURE Grant

Risk Factors of Patients With Diarrhea for Having Clostridioides (Clostridium) difficile Infection.

Nosocomial infections with Clostridioides (Clostridium) difficile have become an emergent health threat. We sought to define risk factors for a C. difficile infection (CDI) beyond the widely known ones, such as antibiotic use and prior hospital stay. We therefore focused on a group of patients with diarrhea in order to identify risk factors for C. difficile infection among this symptomatic cohort. A total of 121 hospitalized patients from Seesen/Germany with diarrhea were included who submitted a stool sample and were interviewed about their socio-demographic background, lifestyle and state of health using a standardized questionnaire. Antibiotic potential of diuretics was examined by agar diffusion test. C. difficile was identified in 29 patients resulting in a prevalence of 24.0%. The infection was hospital-acquired in most cases (p < 0.001, 82.1%; n = 23/28, versus 29/91, 31.9%). The generally accepted risk factor previous antibiotic use was confirmed in this study (p = 0.002, n = 23/28 CDI patients, 82.1%, versus n = 44/91 non-CDI patients, 48.4%). The following additional risk factors were identified: regular consumption of proton pump inhibitors; PPI (p = 0.011, n = 24/29, 82.8% vs. n = 52/92, 56.5%), CDI patients ate less vegetables (p = 0.001, n = 12/29, 41.4% vs. 69/92, 75.0%). The intake of the diuretic agent torasemid in patients with CDI (p = 0.005, n = 18/29, 62.1%) was higher than in patients without (n = 30/92, 32.6%). More patients with CDI had to undergo a surgery in the previous year (p = 0.022, n = 13/29, 44.8% vs. n = 21/92, 22.8%) and held more birds (p = 0.056, n = 4/29, 13.8%) than individuals of the negative group (n = 3/92, 3.3%). In conclusion, although no antibiotic potential was detected in diuretics, especially torasemid seems to have significant influence for the occurrence of a CDI as well as a nutrition poor in vegetables. A diet rich in vegetables represented a fourfold lower risk for a CDI (OR 0.240, CI (0.0720 - 0.796]).

The Cytopathic Effect of Different Toxin Concentrations From Different Clostridioides difficile Sequence Types Strains in Vero Cells.

Clostridioides difficile is one of the leading causes of healthcare-associated diarrhea, with severity ranging from mild, self-limiting disease, to life-threatening toxic megacolon. C. difficile infection (CDI) pathogenesis is mediated by the TcdA and TcdB toxins. This work aimed to draw correlations between toxin levels, bacterial strains, and disease severity in 63 CDI patients. C. difficile typing was performed by multi-locus sequence types (MLST). Toxin concentrations were measured using the TOX A/B test. In addition, cell cytotoxicity assay was performed following Vero cell exposure to stool extracts (24 h). The most prevalent sequence types (ST) were ST2, ST4, ST6, ST13, ST37, ST42, and ST104, with highest toxin levels produced by ST42 and ST104 (302.5 and 297.1 ng/ml, respectively). These strains had a stronger cytopathic effect (CPE) on Vero cells as compared to strains with lower toxin concentrations (p < 0.001), as manifested by lower cell counts and higher percentages of cell rounding and adhesion loss. Although no association was found between ST, toxin concentrations, and disease severity, a diverse in vitro effect of different STs on the viability and activity of Vero cells was observed. These findings suggest that disease severity is affected by both host immune responses and by bacterial characteristics.

Prospective Multicenter Study of Chemotherapy-Induced Clostridium (Clostridioides) difficile Infection in Patients With Lung Cancer: North Japan Lung Cancer Study Group Trial 1204

BackgroundDiarrhea post-antibiotic use is primarily attributed to mucosal lesions induced by Clostridium (Clostridioides) difficile (C. difficile) infection (CDI). Cancer patients undergoing chemotherapy might have a higher risk of CDI even when prior antibiotics are not used. Thus far, the relationship between lung cancer chemotherapy and the incidence of diarrhea remains unclear. This prospective multicenter study aimed to determine the incidence of CDI in lung cancer patients undergoing chemotherapy.MethodsThe presence of C. difficile and its toxins was investigated in lung cancer patients experiencing diarrhea during chemotherapy including paclitaxel (PTX), nanoparticle albumin-bound paclitaxel (nab-PTX), docetaxel (DOC), tegafur-gimeracil-oteracil (S-1), or irinotecan (CPT-11). If grade 2 or higher diarrhea occurred, then a stool culture was performed to detect anaerobic organisms and C. difficile toxins A and B. Additional data were collected through patient interviews and medical chart review.ResultsA total of 263 consecutive patients were enrolled in the study; grade 2 or higher diarrhea was observed in 22 patients (8.4%); CDI was confirmed in five of them (1.9%). The incidence of CDI was 22.7% of all diarrhea cases, and 50% of patients treated with PTX were CDI positive; the incidence of CDI was significantly higher in patients treated with PTX (P=0.039). Among the diarrhea cases, CDI patients had significantly worse ECOG performance status (PS) (P=0.043) and a significantly higher neutrophil count (P=0.028) than non-CDI patients. No CDI patients received antibiotics before cancer chemotherapy.ConclusionsAlthough diarrhea does not always affect a large portion of lung cancer chemotherapy recipients, clinicians should consider the possibility of CDI occurrence in lung cancer patients receiving chemotherapy, particularly PTX, without prior antibiotic exposure.