Nosocomial Infectious Diarrhea Research Articles

A168 RATES OF CLOSTRIDIOIDES DIFFICILE INFECTIONS REQUIRING HOSPITALIZATION DURING THE COVID-19 PANDEMIC

Abstract Background Clostridium difficile infection (CDI) is the most common cause of nosocomial infectious diarrhea and is associated with a substantial burden of morbidity and mortality. Most cases of CDI are acquired through health care setting contacts, where appropriate infection prevention and control (IPC) measures such as contact isolation and proper hand hygiene have been demonstrated to prevent horizontal transmission. Aims We aimed to evaluate whether there was a reduction in CDI-related hospitalizations during the COVID-19 pandemic when an increased emphasis was placed on maintaining IPC measures. Methods We analyzed data from the National Inpatient Sample (NIS) between January 2018 and November 2020. The NIS is the largest publicly available administrative health database in the United States, capturing ampersand:003E7 million hospital admissions annually. All analyses were weighted for the complex survey design of the NIS. Temporal trends in monthly admissions for patients with CDI defined using International Classification of Disease 10th revision codes and excluding patients with established CDI carrier status were evaluated using joinpoint regression. Changes over time were expressed as monthly percent change (MPC). To establish whether temporal changes were related to a reduction in CDI or whether these were more generalized effects due to the pandemic, we compared these temporal trends to rates of hospitalizations for inflammatory bowel disease (IBD) and stroke. Results A total of 1,501,415 CDI admissions were identified. The mean age was 64.6 years and 54.2% of patient’s were female. 4.5% of admissions for CDI were associated with in-hospital mortality. Trends in hospitalization are summarized in Figure 1. Compared to the pre-pandemic period (January 2018-December 2019) CDI-related hospitalizations decreased by 9.1%/month [95% CI: -19.2%, +2.0%] (p=0.12) in early 2020 (January-March 2020). This reduction was not sustained: hospitalizations subsequently increased by +8.0% [95% CI: -4.0%, +21.6%] (p=0.19) in mid-2020 (April-June 2020) and were stable after July 2020 (MPC -0.9% [95% CI: -3.5%, +1.7%], p=0.48). Similar patterns were observed for both IBD and stroke-related hospitalizations. Total hospitalizations per month for CDI were similar by June 2020 as compared to the year preceding the pandemic. Conclusions Although an initial decrease in the rates of CDI hospitalizations were seen early in the pandemic (January-March 2020), this pattern was similarly seen for other chronic and acute conditions, and this has not been sustained long-term. Figure 1. Rates of CDI admissions (2018-2020) Funding Agencies None

Impact of the COVID-19 pandemic on the incidence of healthcare-associated Clostridioides difficile infection in a tertiary healthcare facility in the Republic of Ireland

Clostridioides difficile is the foremost cause of nosocomial infectious diarrhoea and one of the most prevalent healthcare associated infections (HAIs). To investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the incidence of healthcare associated C.difficile infection (HA-CDI). A retrospective study was conducted from January 2019-December 2022 inclusive at a tertiary University Hospital in Dublin, Ireland. The study period was divided into COVID-19 and non-COVID-19 periods determined in tangent with the then national incidences of COVID-19 and number of hospitalized patients with COVID-19. Analyses looked at quantity of testing performed, incidence rates and antimicrobial consumption. An independent samples t-test was used to determine significance between groups. Between COVID-19 and non-COVID-19 periods, no statistically significant difference was observed among HA-CDI rates per 10,000 bed-days (2.1 cases vs 1.76 cases; P=0.34), consumption of defined daily doses per 100 bed-days of antimicrobials - all antimicrobials (83.36 vs 89.5; P=0.091), fluoroquinolones only (3.71 vs 4.46; P=0.067), third-generation cephalosporins only (4.17 vs 4.43; P=0.449), carbapenems only (3.28 vs 3.26; P=0.944) - or the number of C.difficile tests performed per 10,000 bed-days (321.81 tests vs 326.63 tests; P=0.696). There was no difference in the incidence rates of HA-CDI between COVID-19 and non-COVID-19 periods at our institution.

384. Assessing the Multistep Approach for Clostridioides difficile Infection Diagnosis

Abstract Background Clostridioides difficile infection (CDI) is a spore-forming anaerobic Gram-positive bacillus and the leading cause of nosocomial infectious diarrhea. 2017 IDSA/SHEA C. difficile guidelines recommend a multistep algorithm approach for CDI diagnosis. This algorithm entails stool testing via enzyme-linked immunosorbent assay (EIA) for glutamate dehydrogenase (GDH) and C. difficile toxins A/B (Tox). Discordant samples are arbitrated by nucleic acid amplification test (NAAT) for tcdB gene. GDH EIA has sensitivities >90%, while Tox EIA has sensitivities ranging from 50-90%. We aimed to evaluate the diagnostic performance of GDH and Tox EIA using the multistep algorithm as the gold standard. Methods We performed a secondary analysis of an inpatient dataset collected in a tertiary community health system in the Southern US, including 9-months of the incident population from 2019 to 2020. All adults ≥ 18-years old from Princeton Baptist Medical Center (Birmingham, AL) tested for C. difficile were included. Alere TechLab C. difficile Quik Chek Complete® was used to determine GDH and Tox EIA, and Alethia C. difficile DNA Amplification Assay®, a NAAT, for discordant samples. CDI case was defined as positivity for Tox and GDH, or positivity of either Tox or GDH in addition to positive NAAT. Retesting within the same admission was allowed. Results Overall, 288 tests were performed. Concordant positivity for GDH & Tox was found in 29 (10.1%) tests; concordant negativity in 226 (78.5%). Discordant positivity for GDH or Tox was observed in 33 (11.5%) tests; all were tested with NAAT. Only 1 of 33 (3.03%) discordant tests was GDH negative & Tox positive, which had a positive NAAT. The remaining 32 (96.97%) discordant tests were GDH positive and Tox negative, of which 18 (56.3%) were positive for NAAT (Table 1). Performance characteristics for the above tests were calculated (Table 2). Table 1:Clostridioides difficile infection case distributions per GDH and ToxinTable 2:Test performance characteristics Conclusion Taking the multistep algorithm as a gold standard, the performance characteristics of GDH and Tox are concordant to previous descriptions in the literature, with GDH being highly sensitive and Tox being highly specific. A diagnostic algorithm lacking GDH and NAAT would miss over one-third of CDI cases. A diagnostic algorithm lacking Tox and NAAT could potentially overdiagnose about one-fifth of tested patients. Disclosures All Authors: No reported disclosures.

Correlation of Clinical Severity With Stool Microbiome Changes in Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is the world-leading cause of infectious nosocomial diarrhea and pseudomembranous colitis. Antibiotics are the first line of treatment against CDI despite the high likelihood of antibiotic failure and/or recurrence. More data are needed to correlate clinical variables with 16S rRNA microbiome profiles in CDI-infected patients. To determine the relationship(s) between a patient's clinical factors and the stool bacteriome of CDI-positive patients and CDI-negative patients with diarrheal symptoms. This study used stool samples and clinical data from 358 patients with nosocomial diarrhea, who were divided by their CDI diagnosis (CDI-negative: n = 180; CDI-positive; n = 178). The stool bacteriome was profiled by amplicon deep sequencing of the 16S rRNA gene, followed by correlating clinical data. The stool bacteriome was significantly different by severity assessment regardless of CDI status. Phyla and species varied significantly by CDI diagnosis. Severity, defined as a serum white blood cell count greater than 15 cells/μL and/or a creatinine level greater than 1.5 mg/dL, correlated significantly with dysbiosis of the stool bacteriome profile of CDI-positive patients compared to CDI-negative patients. Serum white blood cell count was significantly higher in patients with bacterial dysbiosis, and high levels of creatinine were associated with low bacteriome diversity. Clinical severity of CDI influences the stool microbiome of infected patients. To date, this study has the largest data set comparing 16S rRNA microbiome profiles and clinical variables between CDI-infected and noninfected individuals.

Clostridioides difficile surface layer protein triggered inflammasome activation is mediated by membrane lipid raft

Clostridioides difficile is the leading cause of nosocomial infectious diarrhea, with clinical symptoms ranging from mild diarrhea to pseudomembranous colitis and toxic megacolon. Despite the use of vancomycin and fidaxomicin as standard drugs for the treatment of C. difficileinfection (CDI), clinical relapse rates remain high. Therefore, new alternative therapeutics to treat CDI are urgently required. Surface layer proteins (SLPs) are the most abundant proteins in the C. difficile cell wall, suggesting that they might involve in immune recognition. Here, we found SLPs as well as C. difficile induced inflammasome activation. In addition, the cholesterol‐rich microdomains, lipid rafts, on the cell membrane are thought to be crucial for bacterial adhesion and signal transduction. We demonstrated that lipid rafts participated in C. difficile SLPs binding to the cell membrane. Furthermore, both binding ability and inflammasome activation induced by SLP were abrogated with membrane cholesterol depletion by methyl‐β‐cyclodextrin (MβCD). The coalescence of SLPs in the cholesterol‐rich microdomains was confirmed in C. difficile‐infected cells. Our results demonstrate that SLPs recruit the lipid rafts, which may be a key step for C. difficile colonization and inducing inflammasome activation.

Host Immune Responses to Clostridioides difficile: Toxins and Beyond.

Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

The Role of Toll-Like Receptor-2 in Clostridioides difficile Infection: Evidence From a Mouse Model and Clinical Patients.

Background Clostridioides difficile is the leading cause of nosocomial infectious diarrhea. Toll-like receptors (TLRs) are the major components of innate immunity that sense pathogens. The relationship between TLRs and C. difficile infection (CDI) was analyzed in clinical patients and a mouse model.Materials and MethodsA prospective investigation was conducted in medical wards of Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, from January 2011 to January 2013. Adult patients were followed up for the development of CDI. Single nucleotide polymorphisms (SNPs) of TLR2 and TLR4 were analyzed to assess the relationship between genetic polymorphisms and the development of CDI. A mouse model of CDI was used to investigate the pathogenic role of TLRs in CDI, TLR2 and TLR4 knockout (Tlr2-/- and Tlr4-/-) mice.ResultsIn the prospective study, 556 patients were enrolled, and 6.5% (36) of patients, accounting for 3.59 episodes per 1000 patient-days, developed CDI. Of 539 patients with available blood samples, the TLR2 rs3804099 polymorphism was more often noted in those with CDI than in those without CDI (64.5% vs. 46.1%; P = 0.046) but was not significant in multivariate analysis. Because the TLR2 rs3804099 polymorphism was moderately associated with CDI, the role of TLR2 and TLR4 was further evaluated in a mouse model. Both Tlr2-/- and Tlr4-/- mice showed more severe CDI disease than wild-type mice in terms of body weight change and fecal content five days after oral challenge with C. difficile. Furthermore, Tlr2-/- mice suffered from more severe disease than Tlr4-/- mice, as evidenced by stool consistency, cecum weight, and survival rate.ConclusionThe TLR2 rs3804099 polymorphism is marginally associated with the development of CDI, and the pathogenic role of TLR2 is further supported by a mouse model.

Initial vancomycin versus metronidazole for the treatment of first-episode non-severe Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is the leading cause of infectious nosocomial diarrhea. Although initial fidaxomicin or vancomycin treatment is recommended by most major guidelines to treat severe CDI, there exists varied recommendations for first-episode non-severe CDI. Given the discrepancy in current treatment guidelines, we sought to evaluate the use of initial vancomycin versus metronidazole for first-episode non-severe CDI. We conducted a retrospective cohort study of all adult inpatients with first-episode CDI at our institution from January 2013 to May 2018. The initial vancomycin versus initial metronidazole cohorts were examined using a multivariate logistic regression model. The study cohort of 737 patients had a median age of 72.3 years, and 357 of these patients (48.4%) had hospital-acquired infection. Among 326 patients with non-severe CDI, recurrence, new incident infection, and 30-day mortality rates were 16.2%, 10.9%, and 5.3%, respectively, when treated with initial metronidazole, compared to 20.0%, 1.4%, and 10.0%, respectively, when treated with initial vancomycin. In an adjusted multivariable analysis, the use of initial vancomycin for the treatment of non-severe CDI was associated with a reduction in new incident infection (adjusted odds ratio [ORadj], 0.11; 95% confidence interval [CI], 0.02-0.86; P = .035), compared to initial metronidazole. Initial vancomycin was associated with a reduced rate of new incident infection in the treatment of adult inpatients with first-episode non-severe CDI. These findings support the use of initial vancomycin for all inpatients with CDI, when fidaxomicin is unavailable.

RUTI Resolution After FMT for Clostridioides difficile Infection: A Case Report.

Clostridioides difficile infection (CDI) is the leading cause of nosocomial infectious diarrhea. Fecal microbiota transplantation (FMT) is a successful treatment for recurrent CDI (rCDI), and in some patients FMT has been associated with the resolution of recurrent urinary tract infections (rUTI). Recent evidence suggests that the origin of most bacterial infections in the urinary tract is the gut. Thus, the possibility of using FMT to displace pathogens commonly involved in rUTIs has major therapeutic implications. We report the case of a 93-year-old female patient with a rCDI and rUTI that underwent FMT and reported a complete clinical resolution of CDI; unexpectedly, no new symptomatic UTI episodes were diagnosed post-FMT. We characterized the gut microbiota of the stool donor and of the patient before and after the procedure. Our patient presented a dysbiosis with clear predominance of Enterobacteriaceae (74%) before FMT, which was significantly reduced to 0.07% after FMT. These findings were maintained for almost a year. We also observed an increase in microbial diversity indices compared with the pre-FMT sample reaching diversity values comparable to the donor stool samples. We reasoned that the disappearance of UTIs in our patient resulted from the reduction of Enterobacteriaceae in the gut microbiota. Our findings support previous evidence suggesting the potential of FMT for rUTI, particularly in cases due to multi-drug resistant pathogens where conventional antibiotic treatment is not an option.

A Bundled Approach to Reduce Delayed Testing and Hospital-Acquired Cases of Clostridioides difficile Infection

Background:Clostridioides difficile is a leading cause of nosocomial infectious diarrhea in developed countries, and it has a significant economic impact throughout the world. Early detection of the pathogen and its toxins is critical because early treatment significantly reduces infection-related morbidity, mortality, and medical cost. Surveillance of healthcare-associated infections (HAIs) is conducted using the NHSN standardized infection ratio (SIR). This metric allows comparison of a facility’s observed infection rate to a national benchmark. The SIR can be elevated due to both a lack of institutional criteria for stool submission and the use of highly sensitive but poorly specific testing as a standalone test for diagnosis. The SIR can be artificially elevated by inclusion of C difficile carriers rather than infected patients due to inappropriate testing and overly sensitive methods. We aimed to determine the impact of an institutional nursing-driven protocol for stool submission as well as 2-step testing on the SIR. Methods: Starting from the fourth quarter of 2018, we instituted a nursing protocol for initiation of C. difficile testing. If the patient had ≥3 soft, loose, or liquid stools in 24 hours within the first 3 days of admission, they were placed on contact precautions and an unformed stool sample was submitted for C. difficile nucleic acid amplification testing (NAAT). A positive result prompted further evaluation with a stool enzyme immunoassay toxin test for confirmation of active infection. From hospital day 4 onward, stricter criteria were implemented for testing for C. difficile infection. Data were extrapolated for calculation of a quarterly SIR. This value was then compared to retrospective SIR data from the first quarter of 2016 to the third quarter of 2018. Results: The quarterly total of hospital-onset C. difficile infections from the first quarter of 2016 to the third quarter of 2018 ranged from 24 to 39 incidents per quarter. After implementing the nursing-driven protocol and 2-step testing, the quarterly total of hospital onset C. difficile infections decreased to 5–6 per quarter. The SIR prior to initiation ranged from 0.66 to 1.37 and decreased to 0.306–0.386 after the nursing-driven protocol and 2-step testing were implemented. Conclusions: Implementation of both an institutional nursing-driven protocol for stool submission and a 2-step testing protocol reduced the number of quarterly hospital-onset C. difficile events as well as our facility’s quarterly SIR to below the national standard.Funding: NoneDisclosures: Ioana Chirca, University Hospital

Molecular epidemiology and antimicrobial resistance of Clostridioides difficile detected in chicken, soil and human samples from Zimbabwe

BackgroundClostridioides difficile is the major cause of infectious nosocomial diarrhoea in industrialized nations. Data on the occurrence of C. difficile in Africa, ribotype (RT) distribution, antimicrobial susceptibility patterns and potential zoonotic transmission are scarce. Methods80 Zimbabwean C. difficile isolates from different sources (chicken [n=30], soil [n=21] and humans [n=29]) were investigated using ribotyping, toxin gene detection, resistance testing, multiple-locus variable-number tandem repeat analysis (MLVA), and whole genome sequencing (WGS). ResultsAmong chicken isolates, the most common RTs were RT103 (6/30), RT025 (5/30) and RT070 (4/30). Within soil samples, RT025 and RT056 were most common (3/21 each). In contrast, the non-toxigenic RT084 was most frequently found in human isolates (4/29). Toxin genes were detected in only 19/29 human isolates. Susceptibility testing showed no resistance against metronidazole and vancomycin, and resistance against macrolides and rifampicin was scarce (3/80 and 2/80, respectively); however, 26/80 isolates showed moxifloxacin resistance. MLVA and WGS of strains with identical RTs stemming from different sources revealed clustering of RT025 and RT084 isolates from human und non-human samples. ConclusionNo “hypervirulent” strains were found. The detected clusters between human, chicken and soil isolates indicate ongoing transmission between humans and environmental sources and might point towards a zoonotic potential.

Patient Experiences with Clostridioides difficile Infection: Results of a Canada-Wide Survey.

PurposeClostridioides difficile infection (CDI) is the most prevalent cause of nosocomial infectious diarrhea in Canada and is highly correlated with antibiotic use and contact with health care facilitates. The often-severe symptoms of CDI include diarrhea, dehydration, and abdominal pain. Patients often relapse following symptom resolution, resulting in increased morbidity. Previous research on the impact of CDI centered around the health-care system, clinician perspectives and economic burden, but not on patient experiences. The purpose of this study was to understand the impact of CDI on patients in Canada.MethodsThe Gastrointestinal Society conducted online surveys and gathered data from 167 qualifying participants, who were either patients or their non-treating caregivers. Quantitative parameters were analyzed by descriptive and comparative statistics and contextualized with qualitative insights derived from thematic analysis of open-ended questions.ResultsOur findings, which focused on clinical parameters such as prior exposure to health-care settings, antibiotic use, and patients’ symptoms, mirrored findings from previous research. Interestingly, most surveyed respondents experienced delays in diagnosis and treatment; 29% waited 6–30 days and 10% over 30 days. This delayed diagnosis was further complicated by the report that 62% of respondents did not experience symptom resolution within 7 days of initiating treatment. Importantly, our results suggest a lasting impact after the resolution of CDI and we saw a reduction of self-assessed quality of life from prior to post CDI. Patients’ priorities regarding their experience with CDI focused around concerns about the health-care system, particularly time to diagnosis and treatment, concerns about antibiotic usage and needs from health-care providers.ConclusionThis is the first Canadian report on patients’ experience with CDI. Our data highlight the symptom-related impact on patients and the long-lasting effect on the quality of life including emotional impact. Reducing time to diagnosis and improving patient education are important priorities to attenuate the impact on patients.

Nonalcoholic fatty liver disease as a risk factor for Clostridium difficile-associated diarrhea.

Clostridium difficile is the most common cause of infectious nosocomial diarrhea among adults in developed countries. Nonalcoholic fatty liver disease (NAFLD) is considered the most common chronic liver disease and it is associated with bacterial infections. Our goal was to assess whether NAFLD considered a risk factor for C. difficile-associated diarrhea (CDAD). We conducted a retrospective study of patients admitted with CDAD at Baruch Padeh Medical Center, Poria, Israel during a period of four years. Data on demographic characteristics, clinical signs, underlying conditions, presence of fatty liver based on computed tomography/ultrasonography imaging and several risk factors for CDI were collected. The control group included patients with diarrhea who were negative for CDT and had been hospitalized during the same period. The controls were matched for age (±5 years) and gender. Totally, 115/164 patients with CDAD met the inclusion criteria. The control group was consisted of 115 hospitalized patients with non-CDAD. The mean age of all the participants (230) was 69.57 ± 18 years. NAFLD was found in 76/115 (66%) patients with CDAD vs. 35/115 (30.4%) in the control group, P < 0.001. Moreover, we found significant associations between CDAD group and metabolic syndrome, prior use of antibiotic in the last 3 months, NAFLD and high serum levels of C-reactive protein. Multivariate analysis showed that NAFLD, odds ratio 1.51, 95% confidence interval 1.2-1.95, P = 0.05 was significantly associated with CDAD. This retrospective study showed that NAFLD is a risk factor for CDAD. Moreover, metabolic syndrome and high serum levels of C-reactive protein were significantly associated with the risk of CDAD.

2395. Analysis of Countywide Clostridium difficile Infection using Descriptive Statistics and Geographic Information Systems Mapping

BackgroundClostridium difficile infection (CDI) is now the most common pathogen causing nosocomial infectious diarrhea in the United States, and more than 500,000 people are estimated to have either healthcare-associated (HA) or community acquired (CA) CDI. The epidemiology of CDI is incompletely understood with more than 50% of all CDI cases occurring in the outpatient community and growing at a pace that is greater than HA-CDI.MethodsPatients with CDI within Santa Barbara County, California were identified via three types of tests: Clostridium difficile PCR, gastrointestinal panel by PCR, and enzyme immunoassay (EIA) via local laboratory. Basic patient characteristics were analyzed using descriptive statistics. Changes with CA-CDI incidence were examined on a quarterly basis to identify and compare quarterly trends in CA-CDI incidence. Geographic Information Systems (GIS) mapping was utilized to provide better spatial understanding of disease distribution across communities.ResultsOver 2,000 unique patients with CDI were identified between January 1, 2013 and January 31, 2019. Median age of these patients was 64 years (interquartile range: 45 – 78) and 60% were female. Hot spots of CDI within Santa Barbara County were localized to three major cities: Santa Barbara, Goleta, and Lompoc. Our results show that based on seasonal quarterly data CDI occurred most frequently in winter months.ConclusionIn conclusion, CDI hot spots occurred most frequently during winter months and could possibly be associated with increased antibiotic treatment during flu season. Using the results from this study, we believe that by utilizing spatial and seasonal trends associated with CDI, physicians may be able to identify, diagnose and treat patients with CDI more promptly in Santa Barbara County.Disclosures All authors: No reported disclosures.

2375. Association Between Clostridium difficile Colonization and Inflammatory Bowel Disease Activity

Background Clostridium difficile (CD) is a frequent cause of nosocomial infectious diarrhea. Despite no clear evidence has linked CD colonization (CDC) or CD infection (CDI) with inflammatory bowel disease activity (IBDA), data in our setting has suggested the contrary.MethodsProspective cohort study in a tertiary care hospital in Mexico City. Patients aged ≥18 years with IBD in clinical remission were included between April 2017 and April 2019. Demographic, clinical and laboratory variables, as well as three fecal samples, were collected at inclusion and during follow-up. CDC was defined as a positive GDH test without diarrhea. CDI was defined as diarrhea (as per IDSA criteria) plus positive GDH and PCR tests. IBDA was defined as bloody diarrhea plus a negative GDH test. The primary outcome was the association between CDC and IBDA. Secondary outcomes were incidence rates of CDC and CDI, including risk factors associated with CDC. Univariate and multivariable analyses were performed considering P < 0.05 as statistically significant.ResultsOut of 250 IBD patients, 101 cases met inclusion criteria and 85 completed follow-up (median = 420 days, IQR = 243–511 days). Twenty-three cases (27%) had IBDA during follow-up, eight cases had new CDC (incidence of 8.2/100 person-years), and one case developed CDI (incidence of 1.0/100 person-years). Figure 1 shows the cumulative percentage of cases without CDC during follow-up. In univariate analysis, the following were associated with CDC: decreasing age, decreasing age when IBD was diagnosed, residence in Mexico City or the State of Mexico, and hospitalization during follow-up. In Cox regression analysis, a decreasing age when IBD was diagnosed (HR = 0.92, CI95% = 0.87–0.98, p = 0.009) and residence in the State of Mexico (HR = 5.88, CI 95% = 1.21–28.60, p = 0.028) remained significantly associated with CDC. However, we did not find a statistically significant association between new CDC events and IBDA during a median follow-up period extending beyond 1 year.ConclusionWe found no association between CDC and IBDA. Risk factors associated with CDC were residence in the State of Mexico and a decreasing age when IBD was diagnosed. Disclosures All authors: No reported disclosures.

Risk factors of Clostridium difficile-associated diarrhea in hospitalized adults: Vary by hospitalized duration.

Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Hospitalized patients were at risk of C. difficile-associated diarrhea (CDAD). However the risk factors of CDAD in patients with different hospitalization period are not clear. A prospective investigation was conducted in medical wards of a district hospital in southern Taiwan, from January 2011 to January 2013. We arbitrary divided patients into two groups: hospitalized for at most 14 days and 15-30 days, and analyzed their risk factors for CDAD. Overall 451 patients were enrolled. The multivariable analysis of 19 (8.0%) patients developing CDAD within 14 days' hospital stay and 216 patients hospitalized for≤14 days without CDAD showed malignancy (odds ratio [OR] 7.15, 95% confidence interval [CI] 1.82-28.09; P=0.005), prior cephalosporin (OR 10.8, 95% CI 1.3-93.9; P=0.03) and proton pump inhibitor (PPI; OR 7.1, 95% CI 2.1-24.7; P=0.002) therapy were independently related to CDAD (Table 3), but hypertension (OR 0.2, 95% CI 0.1-0.7; P=0.01) was reversely related to CDAD. However, of 9 (4.2%) patients developing CDAD later (15-30 days' hospital stay) and 207 patients with longer hospitalization (15-30 days) but free of CDAD, malignancy (OR 14.0, 95% CI 1.6-124.9; P=0.02) and underlying diabetes mellitus (OR 20.5, 95% CI 2.9-144.9; P=0.002) were independent risk factors of CDAD. Risk factors for CDAD among hospitalized patients varied by the duration of hospital stay. Intervention strategies to prevent CDAD may be different in terms of hospital stay duration.

Molecular typing of Clostridioides difficile isolates from clinical and non-clinical samples in Iran.

Clostridioides difficile is a major cause of nosocomial infectious diarrhea in hospitalized patients throughout the world. We aimed to characterize C.difficile isolates among hospitalized patients, hospital staffs, and hospital environment samples obtained in three tertiary care hospitals of Iran with regard to their molecular types between June 2016 and November 2017. The toxigenicity of C.difficile isolates was determined by toxigenic culture and multiplex-PCR. Toxigenic C.difficile isolates collected were ribotyped using capillary gel electrophoresis-based PCR and the database of WEBRIBO (http://webribo.ages.at). Of 500 clinical and non-clinical samples, toxigenic C.difficile were identified in 35 of 250 stool samples (14%) and in 3 of 250 swabs (1.2%). The most frequently found ribotypes (RTs) were 039, AI-12, and AI-21 (15.8, 10.52, and 10.52% of all isolates, respectively). Further RTs were: 017, 001, AI-3, AI-15, AI-18, AI-10, AI-4, and PR21195 (as new ribotype). The epidemic RTs (027 and 078) seen in the Europe, North America, and Asia were completely absent in this study.

Rapid Simultaneous Molecular Stool-Based Detection of Toxigenic Clostridioides difficile by Quantitative TaqMan Real-Time PCR Assay.

Clostridioides difficile is a major cause of nosocomial infectious diarrhea in hospitalized patients throughout the world. A multiplex real-time PCR assay was developed and evaluated in comparison with toxigenic culture (TC) (as gold standard method) for direct detection of toxigenic C. difficile in fecal specimens. The multiplex real-time PCR assay simultaneously detected glutamate dehydrogenase (gluD), toxin A (tcdA), toxin B (tcdB), and binary toxin (cdtB) genes in stool samples. The results of multiplex real-time PCR were compared to those of the TC method in 250 patients suspected of C. difficile infection. The prevalence of positive TC was 13.6%. Forty-two stool samples (16.8%) were determined to be gluD+ using multiplex real-time PCR. These included 35 (83.3%) toxigenic (32 tcdA+, tcdB+ and three tcdB+) and 7 (20.0%) were cdtB+. The multiplex real-time PCR assay had a sensitivity of 91.45%, specificity of 99.54%, and positive and negative predictive values of 97% and 98.6%, respectively, compared to the TC method for diagnosis of C. difficile. The analytical sensitivity of the multiplex real-time PCR assay was estimated to be 102 CFU/g of stools and 0.0200 pg of genomic DNA from culture. The analytical specificity was determined to be 100% by using enteric and non-C. difficile standard bacterial strains. The molecular method developed in the study was rapid, sensitive, and specific for detection of toxigenic C. difficile. It is applicable to be performed in clinical laboratories and correlated well with the results obtained by TC.

Cost-Effectiveness Analysis of Bezlotoxumab Added to Standard of Care Versus Standard of Care Alone for the Prevention of Recurrent Clostridium difficile Infection in High-Risk Patients in Spain.

IntroductionClostridium difficile infection (CDI) is the major cause of infectious nosocomial diarrhoea and is associated with considerable morbidity, mortality and economic impact. Bezlotoxumab administered in combination with standard of care (SoC) antibiotic therapy prevents recurrent CDI. This study assessed the cost-effectiveness of bezlotoxumab added to SoC, compared to SoC alone, to prevent the recurrence of CDI in high-risk patients from the Spanish National Health System perspective.MethodsA Markov model was used to simulate the natural history of CDI over a lifetime horizon in five populations of patients at high risk of CDI recurrence according to MODIFY trials: (1) ≥ 65 years old; (2) severe CDI; (3) immunocompromised; (4) ≥ 1 CDI episode in the previous 6 months; and (5) ≥ 65 years old and with ≥ 1 CDI episode in the previous 6 months. The incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed.ResultsIn all patient populations (from 1 to 5), bezlotoxumab added to SoC reduced CDI recurrence compared to SoC alone by 26.4, 19.5, 21.2, 26.6 and 39.7%, respectively. The resulting ICERs for the respective subgroups were €12,724, €17,495, €9545, €7386, and €4378. The model parameters with highest impact on the ICER were recurrence rate (first), mortality, and utility values. The probability that bezlotoxumab was cost-effective at a willingness-to-pay threshold of €21,000/QALY was 85.5%, 54.1%, 86.0%, 94.5%, 99.6%, respectively.ConclusionThe results suggest that bezlotoxumab added to SoC compared to SoC alone is a cost-effective treatment to prevent the recurrence of CDI in high-risk patients. The influence of changes in model parameters on DSA results was higher in patients ≥ 65 years old, with severe CDI and immunocompromised. Additionally, PSA estimated that the probability of cost-effectiveness exceeded 85% in most subgroups.FundingMerck Sharp & Dohme Corp.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0813-y) contains supplementary material, which is available to authorized users.

Germinant Synergy Facilitates Clostridium difficile Spore Germination under Physiological Conditions.

Clostridium difficile is a Gram-positive obligate anaerobe that forms spores in order to survive for long periods in the unfavorable environment outside a host. C. difficile is the leading cause of nosocomial infectious diarrhea worldwide. C. difficile infection (CDI) arises after a patient treated with broad-spectrum antibiotics ingests infectious spores. The first step in C. difficile pathogenesis is the metabolic reactivation of dormant spores within the gastrointestinal (GI) tract through a process known as germination. In this work, we aim to elucidate the specific conditions and the location within the GI tract that facilitate this process. Our data suggest that C. difficile germination occurs through a two-step biochemical process that is regulated by pH and bile salts, amino acids, and calcium present within the GI tract. Maximal germination occurs at a pH ranging from 6.5 to 8.5 in the terminal small intestine prior to bile salt and calcium reabsorption by the host. Germination can be initiated by lower concentrations of germinants when spores are incubated with a combination of bile salts, calcium, and amino acids, and this synergy is dependent on the availability of calcium. The synergy described here allows germination to proceed in the presence of inhibitory bile salts and at physiological concentrations of germinants, effectively decreasing the concentrations of nutrients required to initiate an essential step of pathogenesis.IMPORTANCEClostridium difficile is an anaerobic spore-forming human pathogen that is the leading cause of nosocomial infectious diarrhea worldwide. Germination of infectious spores is the first step in the development of a C. difficile infection (CDI) after ingestion and passage through the stomach. This study investigates the specific conditions that facilitate C. difficile spore germination, including the following: location within the gastrointestinal (GI) tract, pH, temperature, and germinant concentration. The germinants that have been identified in culture include combinations of bile salts and amino acids or bile salts and calcium, but in vitro, these function at concentrations that far exceed normal physiological ranges normally found in the mammalian GI tract. In this work, we describe and quantify a previously unreported synergy observed when bile salts, calcium, and amino acids are added together. These germinant cocktails improve germination efficiency by decreasing the required concentrations of germinants to physiologically relevant levels. Combinations of multiple germinant types are also able to overcome the effects of inhibitory bile salts. In addition, we propose that the acidic conditions within the GI tract regulate C. difficile spore germination and could provide a biological explanation for why patients taking proton pump inhibitors are associated with increased risk of developing a CDI.