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BackgroundIn Clostridioides difficile infection (CDI), the relationship between clinical, microbial, and temporal/epidemiological trends, disease severity and adverse outcomes is incompletely understood. In a follow-up to our study from 2010–2013, we evaluate stool toxin levels and C. difficile polymerase chain reaction (PCR) ribotypes. We hypothesized that elevated stool toxins and infection with ribotype 027 associate with adverse outcomes.MethodsIn 565 subjects at the University of Michigan with CDI diagnosed by positive testing for toxins A/B by enzyme immunoassay (EIA) or PCR for the tcdB gene, we quantified stool toxin levels via a modified cell cytotoxicity assay (CCA), isolated C. difficile by anaerobic culture, and performed PCR ribotyping. Severe CDI was defined by Infectious Diseases Society of America (IDSA) criteria, and primary outcomes were all-cause 30-day mortality and a composite of colectomy, intensive care unit admission, and/or death attributable to CDI within 30 days. Analyses included bivariable tests and logistic regression.Results199 samples were diagnosed by EIA; 447 were diagnosed by PCR. Toxin positivity associated with IDSA severity but not primary outcomes. In 2016, compared with 2010–2013, ribotype 106 newly emerged, accounting for 10.6% of strains, ribotype 027 fell from 16.5% to 9.3%, and ribotype 014–027 remained stable at 18.9%. Ribotype 014–020 associated with IDSA severity and 30-day mortality (P = .001).ConclusionsToxin positivity by EIA and CCA associated with IDSA severity but not with subsequent adverse outcomes. The molecular epidemiology of C. difficile has shifted, which may have implications for the optimal diagnostic strategy for and clinical severity of CDI.

BackgroundKlebsiella commonly colonizes the intestinal tract of hospitalized patients and is a leading cause of healthcare-associated infections. Colonization is associated with subsequent infection, but the factors determining this progression are unclear.MethodsIntensive care and hematology/oncology patients were screened for Klebsiella colonization by rectal swab culture and monitored for infection for 90 days after a positive swab. Electronic medical records were analyzed for patient factors associated with subsequent infection, and variables of potential significance in bivariable analysis were used to build a final multivariable model. Concordance between colonizing and infecting isolates was assessed by wzi capsular gene sequencing.ResultsAmong 2087 hospital encounters from 1978 colonized patients, 90 cases of infection (4.3%) were identified. Mean time to infection was 20.6 ±24.69 (range 0-91, median 11.5) days. Of 86 typed cases, 68 unique wzi types were identified and 69 cases (80.2%) were colonized with an isolate of the same type prior to infection. Based on multivariable modeling, overall comorbidities, depression and low albumin level at the time of rectal swab were independently associated with subsequent Klebsiella infection.ConclusionsDespite the high diversity of colonizing strains of Klebsiella, there is high concordance with subsequent infecting isolates and progression to infection is relatively quick. Readily accessible data from the medical record could be used by clinicians to identify colonized patients at increased risk of subsequent Klebsiella infection.ImportanceKlebsiella is a leading cause of healthcare-associated infections. Patients who are intestinally colonized with Klebsiella are at significantly increased risk of subsequent infection, but only a subset of colonized patients progress to disease. Colonization offers a potential window of opportunity to intervene and prevent these infections, if the patients at greatest risk could be identified. To identify patient factors associated with infection in colonized patients, we studied 1978 colonized patients. We found that patients with a higher burden of underlying disease in general, depression in particular, and low albumin in a blood test were more likely to be a case of infection. However, these variables did not completely predict infection, suggesting that other host and microbial factors may also be important. The average time to infection was 3 weeks, suggesting that there is time to intervene and prevent Klebsiella infections in hospitalized patients.

This article concerns the PhysioNet/Computing in Cardiology Challenge 2020 which focused on building computational methods to identify cardiac abnormalities from 12-lead ECGs. Our team, MCIRCC, utilized a large secondary dataset of 12-lead ECGs obtained from the Section of Electrophysiology at the University of Michigan, called the MUSE dataset, to pre-train multiple residual neural networks that were later re-trained on the challenge dataset. To do so, the diagnosis statements that existed in our dataset were utilized to assign the same labels to our ECGs as the challenge data. After parameter optimization, we selected a subset of top performing models and created an ensemble model that achieved a challenge validation score of 0.616, and full test score of 0.141, placing us 27th out of 41 teams in the official ranking.

Background:Clostridioides difficile infection (CDI) frequently recurs after initial treatment. Predicting recurrent CDI (rCDI) early in the disease course can assist clinicians in their decision making and improve outcomes. However, predictions based on clinical criteria alone are not accurate and/or do not validate other results. Here, we tested the hypothesis that circulating and stool-derived inflammatory mediators predict rCDI. Methods: Consecutive subjects with available specimens at diagnosis were included if they tested positive for toxigenic C. difficile (+enzyme immunoassay [EIA] for glutamate dehydrogenase and toxins A/B, with reflex to PCR for the tcdB gene for discordants). Stool was thawed on ice, diluted 1:1 in PBS with protease inhibitor, centrifuged, and used immediately. A 17-plex panel of inflammatory mediators was run on a Luminex 200 machine using a custom antibody-linked bead array. Prior to analysis, all measurements were normalized and log-transformed. Stool toxin activity levels were quantified using a custom cell-culture assay. Recurrence was defined as a second episode of CDI within 100 days. Ordination characterized variation in the panel between outcomes, tested with a permutational, multivariate ANOVA. Machine learning via elastic net regression with 100 iterations of 5-fold cross validation selected the optimal model and the area under the receiver operator characteristic curve (AuROC) was computed. Sensitivity analyses excluding those that died and/or lived >100 km away were performed. Results: We included 186 subjects, with 95 women (51.1%) and average age of 55.9 years (±20). More patients were diagnosed by PCR than toxin EIA (170 vs 55, respectively). Death, rCDI, and no rCDI occurred in 32 (17.2%), 36 (19.4%), and 118 (63.4%) subjects, respectively. Ordination revealed that the serum panel was associated with rCDI (P = .007) but the stool panel was not. Serum procalcitonin, IL-8, IL-6, CCL5, and EGF were associated with recurrence. The machine-learning models using the serum panel predicted rCDI with AuROCs between 0.74 and 0.8 (Fig. 1). No stool inflammatory mediators independently predicted rCDI. However, stool IL-8 interacted with toxin activity to predict rCDI (Fig. 2). These results did not change significantly upon sensitivity analysis. Conclusions: A panel of serum inflammatory mediators predicted rCDI with up to 80% accuracy, but the stool panel alone was less successful. Incorporating toxin activity levels alongside inflammatory mediator measurements is a novel, promising approach to studying stool-derived biomarkers of rCDI. This approach revealed that stool IL-8 is a potential biomarker for rCDI. These results need to be confirmed both with a larger dataset and after adjustment for clinical covariates.Funding: NoneDisclosure: Vincent Young is a consultant for Bio-K+ International, Pantheryx, and Vedanta Biosciences.

Background Clostridium difficile infection (CDI) has high incidence in the United States, but less so in East Asian countries such as Taiwan. The reason for this is not understood, but microbial studies could reveal important epidemiologic insights. We hypothesized that the circulating strains of C. difficile and the gut microbiota differ between the United States and Taiwan. Methods Patients with diarrhea ± CDI from the University of Michigan and Chang Gung Memorial Hospital were included. CDI was defined by + enzyme immunoassay for the glutamate dehydrogenase gene and toxins A/B, with reflex to tcdB gene PCR for discordants. C. difficile was isolated by anaerobic culture and characterized by PCR ribotype. The fecal microbiota was assessed by sequence analysis of 16S rRNA-encoding gene amplicons targeting the V4 region. Amplicon sequences were processed using the mothur bioinformatics pipeline, with an operational taxonomic unit (OTU) defined by < = 3% sequence homology. Analysis was performed via logistic regression, principal coordinates (PCoA), and ANOVA. Results Community diversity by Shannon index of CDI- patients was lower (Figure 1); this difference was greater in Taiwan (P < .001, OR = 3.9 per unit Shannon). Taiwanese CDI- patients had lower Bacteroidetes relative abundance (RA) (Figure 2). The Taiwanese CDI- group also differed on PCoA and ANOVA (Figure 3, P < .001). OTU1 (genus Firmicutes) was depleted in CDI+ patients (P < .001, OR = 0.69 per 10% RA increase). Circulating ribotypes (Table 1) differ between countries, with no epidemic strains (R027/R078) present in Taiwan (P = .027). R027 and 014/020 comprised > 50% of US isolates while > 50% of Taiwanese isolates were R002. Conclusion Taiwan and US CDI+ patients differ in dominant ribotypes. It is overall difficult to differentiate diarrheal CDI+ and CDI- patients by the microbiome. Taiwanese CDI- patients are outliers, and possible reasons (e.g., differential burden of parasitic infection; diet) require further study. The increased diversity and lower Bacteroidetes in CDI+ vs. CDI- diarrheal patients contrast with prior studies that instead compared with CDI- non-diarrheal patients. Circulating strains in Taiwan include no epidemic variants; whether this explains the differential incidence needs further study. Disclosures All authors: No reported disclosures.

Background The optimal diagnostic strategy for Clostridium difficile infection (CDI) is not known, and no test is shown to clearly differentiate colonization from symptomatic infection. We hypothesized that detection and/or quantification of stool toxins would associate with severe disease and adverse outcomes. Methods We conducted a retrospective cohort study among subjects with CDI diagnosed in 2016 at the University of Michigan. The clinical microbiology laboratory tested for glutamate dehydrogenase antigen and toxins A/B by enzyme immunoassay (EIA). Discordant results reflexed to PCR for the tcdB gene. Stool toxin levels were quantified via a modified cell cytotoxicity assay (CCA). C. difficile was isolated by anaerobic culture and ribotyped. Severe CDI was defined by the IDSA criteria: white blood cell count >15,000 cells/µL or a 1.5-fold increase in serum creatinine above baseline. The primary outcomes were all-cause 30-day mortality and a composite of colectomy, ICU admission, and/or death attributable to CDI within 30 days. Analysis included standard bivariable tests and adjusted models via logistic regression. Results From 565 adult patients, we obtained 646 samples; 199 (30.8%) contained toxins by EIA. Toxin positivity associated with IDSA severity (Table 1), but not our primary outcomes on unadjusted analysis. After adjustment for putative confounders, we still did not observe an association between toxin positivity and our primary outcomes. Stool toxin levels by CCA >6.4 ng/mL associated with IDSA severity (Table 1), but not the primary outcomes. Compared with the period from 2010 to 2013, the circulating ribotypes of C. difficile at our institution changed in 2016. Notably ribotype 106 newly emerged, accounting for 10.6% of strains, and ribotype 027 fell to 9.3% (Table 2). The incidence of ribotype 014-027 has remained stable at 18.9%, but this strain was associated with both IDSA severity and 30-day mortality (OR = 3.32; P = 0.001). Conclusion Toxin detection by EIA/CCA associated with IDSA severity, but this study was unable to confirm an association with subsequent adverse outcomes. The molecular epidemiology of C. difficile has shifted, and this may have implications for the optimal diagnostic strategy for CDI. Disclosures All authors: No reported disclosures.