The changing epidemiology of Clostridioides difficile infection and the NAP1/027 strain in two Québec hospitals: a 17-year time-series study.

Objective: To describe the epidemiology of healthcare-associated Clostridioides difficile infection (HA-CDI) in two Québec hospitals in Canada following the 2003 epidemic and to evaluate the impact of antibiotic stewardship on the incidence of HA-CDI and the NAP1/027 strain. Design: Time-series analysis. Setting: Two Canadian tertiary care hospitals based in Montréal, Québec. Patients: Patients with a positive assay for toxigenic C. difficile were identified through infection control surveillance. All cases of HA-CDI, defined as symptoms occurring after 72 hours of hospital admission or within 4 weeks of hospitalization, were included. Methods: The incidence of HA-CDI and antibiotic utilization from 2003 to 2020 were analyzed with available C. difficile isolates. The impact of antibiotic utilization on HA-CDI incidence was estimated by a dynamic regression time-series model. Antibiotic utilization and the proportion of NAP1/027 strains were compared biannually for available isolates from 2010 to 2020. Results: The incidence of HA-CDI decreased between 2003 and 2020 at both hospitals from 26.5 cases per 10,000 patient-days in 2003 to 4.9 cases per 10,000 patient-days in 2020 respectively. Over the study period, there were an increase in the utilization of third-generation cephalosporins and a decrease in usage of fluoroquinolones and clindamycin. A decrease in fluoroquinolone utilization was associated with a significant decrease in HA-CDI incidence as well as decrease in the NAP1/027 strain by approximately 80% in both hospitals. Conclusions: Decreased utilization of fluoroquinolones in two Québec hospitals was associated with a decrease in the incidence of HA-CDI and a genotype shift from NAP1/027 to non-NAP1/027 strains.

Comparison of rectal swabs and fecal samples for the detection of Clostridioides difficile infections with a new in-house PCR assay.

The detection of Clostridioides difficile infections (CDI) relies on testing the stool of patients by toxin antigen detection or PCR methods. Although PCR and antigenic methods have significantly reduced the time to results, delays in stool collection can significantly add to the turnaround time. The use of rectal swabs to detect C. difficile could considerably reduce the time to diagnosis of CDI. We developed a new rapid PCR assay for the detection of C. difficile and evaluated this PCR assay on both stool and rectal swab specimens. We recruited a total of 623 patients suspected of C. difficile infection. Stool samples and rectal swabs were collected from each patient and tested by our PCR assay. Stool samples were also tested by the cell cytotoxicity neutralization assay (CCNA) as a reference. The PCR assay detected C. difficile in 60 stool specimens and 61 rectal swabs for the 64 patients whose stool samples were positive for C. difficile by CCNA. The PCR assay detected an additional 35 and 36 stool and rectal swab specimens positive for C. difficile, respectively, for sensitivity with stools and rectal swabs of 93.8% and 95.3%, specificity of 93.7% and 93.6%, positive predictive values of 63.2% and 62.9%, and negative predictive values of 99.2% and 99.4%. Detection of C. difficile using PCR on stools or rectal swabs yielded reliable and similar results. The use of PCR tests on rectal swabs could reduce turnaround time for CDI detection, thus improving CDI management and control of C. difficile transmission. IMPORTANCE: Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea, resulting in high morbidity, mortality, and economic burden. In clinical laboratories, CDI testing is currently performed on stool samples collected from patients with diarrhea. However, the diagnosis of CDI can be delayed by the time required to collect stool samples. Barriers to sample collection could be overcome by using a rectal swab instead of a stool sample. Our study showed that CDI can be identified rapidly and reliably by a new PCR assay developed in our laboratory on both stool and rectal swab specimens. The use of PCR tests on rectal swabs could reduce the time for the detection of CDI and improve the management of this infection. It should also provide a useful alternative for infection-control practitioners to better control the spread of C. difficile.

Preventing Potential Patient Harm Through Clinical Content Interventions During Oncology Clinical Trial Implementation.

OBJECTIVES: Clinical trial documents are complex and may have inconsistencies, leading to potential site implementation errors and may compromise participant safety. This study characterizes the frequency and type of administrative and potential patient safety interventions (PPSIs) made during the review of oncology trial documents for clinical trial implementation by centralized clinical content specialists. METHODS: A dedicated group of centralized clinical content specialists reviewed trial documents, including the protocol, laboratory manual, and pharmacy/cellular therapy manual, and collected intervention data over a 1-year period. Each trial was categorized by study phase and sponsor type, and multiple interventions could be identified per trial. Interventions were deemed administrative or PPSIs, with PPSIs further subcategorized as medication, laboratory, procedure related, or other. RESULTS: Of 585 clinical trials reviewed, 269 (46%) required intervention(s). Among 1001 interventions, 171 (17.1%) were PPSIs. Most PPSIs were medication related (45.6%), with drug dosing interventions most frequently identified (53.8%). Phase 1 trials had the highest proportion of PPSIs (0.35:1) and administrative interventions (2:1) per trial compared with all other phases. Investigator-initiated trials saw the highest proportion of PPSIs per trial (0.44:1) of all sponsor types. CONCLUSIONS: This study demonstrates a gap in patient safety when assessing trial documents for clinical trial implementation. One solution to address this gap is the utilization of a centralized team of clinical specialists to preemptively review trial documents, thereby enhancing patient safety during clinical trial conduct.

A nested cohort 5-year Canadian surveillance of Gram-negative antimicrobial resistance for optimized antimicrobial therapy.

We analyzed 5 years (2016-2020) of nested Canadian data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) to identify pathogen predominance and antimicrobial resistance (AMR) patterns of adult Gram-negative infections in Canadian health care and to complement other public surveillance programs and studies in Canada. A total of 6853 isolates were analyzed from medical (44%), surgical (18%), intensive care (22%) and emergency units (15%) and from respiratory tract (36%), intra-abdominal (25%), urinary tract (24%) and bloodstream (15%) infections. Overall, E. coli (36%), P. aeruginosa (18%) and K. pneumoniae (12%) were the most frequent isolates and P. aeruginosa was the most common respiratory pathogen. 18% of Enterobacterales species were ESBL positive. Collective susceptibility profiles showed that P. aeruginosa isolates were highly susceptible (> 95%) to ceftolozane/tazobactam and colistin, though markedly less susceptible (58-74%) to other antimicrobials tested. Multi-drug resistance (MDR) was present in 10% of P. aeruginosa isolates and was more frequent in those from respiratory infections and from ICU than non-ICU locations. Of P. aeruginosa isolates that were resistant to combinations of ceftazidime, piperacillin/tazobactam and meropenem, 73-96% were susceptible to ceftolozane/tazobactam over the period of the study. These national data can now be combined with clinical prediction rules and genomic data to enable expert antimicrobial stewardship applications and guide treatment policies to optimize adult patient care.

Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma.

BACKGROUND: Preclinical evidence demonstrating circadian rhythmicity within the immune system provides a rationale for hypothesis that immune checkpoint inhibitor (ICI) infusion time-of-day may serve as an actionable mechanism to improve outcomes. Herein, we explore the association between ICI time of infusion (TOI) and outcomes in metastatic renal cell carcinoma (mRCC). METHODS: Data from patients with mRCC who received nivolumab or nivolumab/ipilimumab, in first- or second-line were retrospectively collected. Patients who received < 20% of infusions after 16:30 were assigned to the early TOI sub-cohort, while the rest were assigned to the late TOI sub-cohort. Clinical outcomes were compared across the 2 groups. RESULTS: Among 135 patients included, 89 (65.9%) and 46 (34.1%) were assigned to early and late TOI sub-cohorts, respectively. Baseline characteristics were comparable across the 2 sub-cohorts. Objective response rate (ORR) was 36.0% with early TOI versus 29.5% with late TOI (P = .157). Median time to treatment failure (TTF) was 9.5 months in the early TOI sub-cohort versus 4.6 months in the late TOI sub-cohort with a hazard ratio (HR) of 1.405 (95% CI, 0.919-2.149; P = .11) in univariate analysis and 1.694 (95% CI, 1.064-2.698; P = .026) in multivariate analysis. Higher cut offs allocating patients into the late TOI sub-cohort yielded an incremental increase in the HR for TTF and overall survival (OS) that reached statistical significance. CONCLUSIONS: In patients with mRCC, early TOI yielded a numerical increase in ORR, TTF and OS, with the TTF difference reaching significance in multivariate analysis. Prospective randomized studies are warranted to examine the impact of chronomodulation on outcomes with ICIs in mRCC.

Diagnostic yield of serial SARS-CoV-2 testing in hospitalized patients.

BACKGROUND: The detection rate of SARS-CoV-2 by polymerase chain reaction (PCR) varies depending on the time since exposure and is highest around the time of symptom onset. It is conceivable that patients who are incubating SARS-CoV-2 may screen negative at admission and develop transmissible but undetected asymptomatic or pre-symptomatic disease while in hospital. The incidence of COVID-19 in Montreal, Canada started to increase in December 2020. In anticipation of a much larger rise after the holiday period, the McGill University Health Centre implemented serial SARS-CoV-2 testing for all admitted patients on day 5 and 10 after admission, to evaluate the clinical utility of serial SARS-CoV-2 testing among patients who test negative on admission screening. METHODS: We retrospectively analyzed the diagnostic yield of SARS-CoV-2 serial testing for patients admitted between January 4, 2021 and April 30, 2021. RESULTS: A total of 1,505 patients underwent serial testing at day 5 and 841 patients underwent serial testing at day 10. Only 10 patients were positive on serial testing at day 5 and only 12 patients were positive on serial testing at day 10, for a yield at day 5 and day 10 of 0.7% and 1.4%, respectively. CONCLUSIONS: The yield of serial SARS-CoV-2 testing was 0.7% at day 5 and 1.4% at day 10. We found that the yield of serial testing was higher when the community incidence was higher and could be considered in this situation. Policies which target repeat testing towards symptomatic or exposed individuals appear to be effective in identifying those with a positive test while admitted but testing negative upon admission.

HISTORIQUE: Le taux de détection du SRAS-CoV-2 par l'amplification en chaîne par polymérase (PCR) varie en fonction de la période écoulée depuis l'exposition et est plus élevé aux alentours du moment d'apparition des symptômes. Il se peut que les patients en période d'incubation du SRAS-CoV-2 obtiennent un résultat négatif à leur admission, puis développent une maladie asymptomatique ou présymptomatique non détectée pendant leur séjour hospitalier. L'incidence de COVID-19 a commencé à augmenter à Montréal, au Canada, en décembre 2020. En prévision d'une hausse beaucoup plus marquée après la période des fêtes, le Centre universitaire de santé McGill a mis en œuvre des tests sériels du SRAS-CoV-2 pour tous les patients hospitalisés le cinquième et le dixième jour après leur hospitalisation, afin d'évaluer l'utilité clinique des tests sériels du SRAS-CoV-2 chez les patients qui avaient reçu un résultat négatif lors du dépistage à leur admission. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective du taux diagnostique des tests sériels du SRAS-CoV-2 chez les patients hospitalisés entre le 4 janvier et le 30 avril 2021. RÉSULTATS: Au total, 1 505 patients se sont soumis au test sériel le cinquième jour et 841 patients, le dixième jour. Seulement dix patients ont obtenu un résultat positif au test sériel le cinquième jour (0,7 %) et seulement 12, le dixième jour (1,4 %). CONCLUSIONS: Le taux de résultats positifs aux tests sériels du SRAS-CoV-2 s'élevait à 0,7 % le cinquième jour et à 1,4 % le dixième jour. Il était plus marqué lorsque l'incidence communautaire était plus élevée; les tests sériels pourraient être envisagés dans cette situation. Les politiques qui ciblent les tests répétés chez les personnes symptomatiques ou exposées semblent efficaces pour détecter celles dont le résultat est positif pendant leur hospitalisation, mais qui ont obtenu un résultat négatif à leur admission.

Detection of Free Toxin B in the Stool of Asymptomatic Clostridioides difficile Carriers by the Cell Cytotoxicity Neutralization Assay.

Cell cytotoxicity neutralization assay (CCNA) is considered to be a gold standard to diagnose Clostridioides difficile infections. We performed CCNA on 77 consecutive admission screening rectal swabs from asymptomatic toxigenic C. difficile carriers. Thirty-nine percent of specimens from asymptomatic carriers were positive. Thus, CCNA specificity may be lower than previously thought.

Fecal host biomarkers predicting severity of Clostridioides difficile infection.

Clostridioides difficile is a major cause of health care-associated diarrhea. Severity ranges from mild to life-threatening, but this variability remains poorly understood. Microbiologic diagnosis of C. difficile infection (CDI) is straightforward but offers little insight into the patient's prognosis or into pathophysiologic determinants of clinical trajectory. The aim of this study was to discover host-derived, CDI-specific fecal biomarkers involved in disease severity. Subjects without and with CDI diarrhea were recruited. CDI severity was based on Infectious Diseases Society of America/Society for Healthcare Epidemiology of America criteria. We developed a liquid chromatography tandem mass spectrometry approach to identify host-derived protein biomarkers from stool and applied it to diagnostic samples for cohort-wise comparison (CDI-negative vs. nonsevere CDI vs. severe CDI). Selected biomarkers were orthogonally confirmed and subsequently verified in a CDI mouse model. We identified a protein signature from stool, consisting of alpha-2-macroglobulin (A2MG), matrix metalloproteinase-7 (MMP-7), and alpha-1-antitrypsin (A1AT), that not only discriminates CDI-positive samples from non-CDI ones but also is potentially associated with disease severity. In the mouse model, this signature with the murine homologs of the corresponding proteins was also identified. A2MG, MMP-7, and A1AT serve as biomarkers in patients with CDI and define novel components of the host response that may determine disease severity.

Increased Community-Associated Clostridioides difficile Infections in Quebec, Canada, 2008-20151.

The annual incidence rate of community-associated Clostridioides difficile infections in Quebec, Canada, has increased by 33.3%, from 0.51 (2008) to 0.68 (2015) cases/100,000 population, while incidence of healthcare-associated cases remained relatively stable. Possible causes include increased disease severity, increased antimicrobial drug use, emergence of virulent strains, and heightened physician awareness.

Predictors of Clostridioides difficile Infection Among Asymptomatic, Colonized Patients: A Retrospective Cohort Study.

BACKGROUND: Asymptomatic patients colonized with Clostridioides difficile are at risk of developing C. difficile infection (CDI), but the factors associated with disease onset are poorly understood. Our aims were to identify predictors of hospital-onset CDI (HO-CDI) among colonized patients and to explore the potential benefits of primary prophylaxis to prevent CDI. METHODS: We conducted a retrospective cohort study in a tertiary academic institution. Colonized patients were identified by detecting the tcdB gene by polymerase chain reaction on a rectal swab. Univariate and multivariate logistic regression analyses were used to identify predictors of HO-CDI. RESULTS: There were 19 112 patients screened, from which 960 (5%) colonized patients were identified: 513 met the inclusion criteria. Overall, 39 (7.6%) developed a HO-CDI, with a 30-day attributable mortality of 15%. An increasing length of stay (adjusted odds ratio [aOR] per day, 1.03; P = .006), exposure to multiple classes of antibiotics (aOR per class, 1.45; P = .02), use of opioids (aOR, 2.78; P = .007), and cirrhosis (aOR 5.49; P = .008) were independently associated with increased risks of HO-CDI, whereas the use of laxatives was associated with a lower risk of CDI (aOR 0.36; P = .01). Among the antimicrobials, B-lactam with B-lactamase inhibitors (OR 3.65; P < .001), first-generation cephalosporins (OR 2.38; P = .03), and carbapenems (OR 2.44; P = .03) correlated with the greatest risk of HO-CDI. By contrast, patient age, the use of proton pump inhibitors, and the use of primary prophylaxis were not significant predictors of HO-CDI. CONCLUSIONS: This study identifies several factors that are associated with CDI among colonized patients. Whether modifying these variables could decrease the risk of CDI should be investigated.

A Multicenter Study of the Revogene C. difficile System for Detection of the Toxin B Gene from Unformed Stool Specimens.

Clostridioides difficile is the leading cause of diarrhea in hospitalized U.S. patients and results in over 400,000 cases of C. difficile infection per year. C. difficile infections have mortality rates of 6 to 30% and significantly increase health care costs, because of increased length of stay and increased frequency of readmissions due to recurrences. Efforts to reduce the spread of C. difficile in hospitals have led to the development of rapid sensitive diagnostic methods. A multicenter study was performed to establish the performance characteristics of the Revogene C. difficile test (Meridian Bioscience, Cincinnati, OH, USA) for use in detection of the toxin B (tcdB) gene from toxigenic C. difficile The Revogene instrument is a new molecular platform that uses real-time PCR to detect nucleic acids in up to 8 specimens at a time. A total of 2,461 specimens from symptomatic patients that had been submitted for C. difficile testing were enrolled at 7 sites throughout the United States and Canada for evaluation of the assay. Each stool specimen was tested for the presence of the tcdB gene using the Revogene C. difficile test, and results were compared with those of the reference method, a combination of direct and enriched culture methods. Overall, the Revogene C. difficile test demonstrated a sensitivity of 85.0% (95% confidence interval, 80% to 88%) and a specificity of 97.2% (95% confidence interval, 96% to 98%). The Revogene C. difficile test, using clinical stool specimens for detection of tcdB in C. difficile, demonstrated acceptable sensitivity and specificity, with a short turnaround time.

The infectious thyroid nodule: a case report of mucormycosis associated with ibrutinib therapy.

BACKGROUND: Acute invasive fungal infections of the head and neck secondary to tyrosine kinase inhibitors are rare and potentially life-threatening events. CASE PRESENTATION: We report a case of mucormycosis of the thyroid gland in a patient known for chronic lymphocytic leukemia receiving ibrutinib who presented with a rapidly growing thyroid nodule and dysphonia. An acute invasive fungal infection was identified on a core needle biopsy; mucormycosis was confirmed on culture. The patient was successfully treated with surgical debridement and long-term antifungal therapy. CONCLUSION: Patients on ibrutinib may be at risk of acute invasive fungal infections of the head and neck.

First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options.

Until recently, a dichotomy existed in the front-line approach of metastatic clear-cell renal cell carcinoma (mRCC). Specifically, patients received either targeted therapy or immunotherapy. Targeted therapy entailed use of agents blocking signaling through the vascular endothelial growth factor (VEGF) receptor, such as cabozantinib, sunitinib, or pazopanib. Immunotherapy entailed dual therapy with nivolumab and ipilimumab, both checkpoint inhibitors for intermediate/poor International Metastatic RCC Database Consortium (IMDC)-risk disease patients. Within the past year, two datasets have emerged that led to recent approvals of combined therapy with VEGF and checkpoint inhibitors. These regimens (axitinib with either avelumab or pembolizumab) are among several that have been or will be evaluated for patients with newly diagnosed mRCC. We aim to facilitate treatment decisions through this comprehensive and contextualized overview of recent datasets in this therapeutic space.

Clostridium difficile: Investigating Transmission Patterns Between Infected and Colonized Patients Using Whole Genome Sequencing.

Background: Whole genome sequencing (WGS) studies can enhance our understanding of the role of patients with asymptomatic Clostridium difficile colonization in transmission. Methods: Isolates obtained from patients with Clostridium difficile infection (CDI) and colonization identified in a study conducted during 2006-2007 at 6 Canadian hospitals underwent typing by pulsed-field gel electrophoresis, multilocus sequence typing, and WGS. Isolates from incident CDI cases not in the initial study were also sequenced where possible. Ward movement and typing data were combined to identify plausible donors for each CDI case, as defined by shared time and space within predefined limits. Proportions of plausible donors for CDI cases that were colonized, infected, or both were examined. Results: Five hundred fifty-four isolates were sequenced successfully, 353 from colonized patients and 201 from CDI cases. The NAP1/027/ST1 strain was the most common strain, found in 124 (62%) of infected and 92 (26%) of colonized patients. A donor with a plausible ward link was found for 81 CDI cases (40%) using WGS with a threshold of ≤2 single nucleotide polymorphisms to determine relatedness. Sixty-five (32%) CDI cases could be linked to both infected and colonized donors. Exclusive linkages to infected and colonized donors were found for 28 (14%) and 12 (6%) CDI cases, respectively. Conclusions: Colonized patients contribute to transmission, but CDI cases are more likely linked to other infected patients than colonized patients in this cohort with high rates of the NAP1/027/ST1 strain, highlighting the importance of local prevalence of virulent strains in determining transmission dynamics.

Detection and Isolation of Clostridium difficile Asymptomatic Carriers During Clostridium difficile Infection Outbreaks: An Exploratory Study.

During 4 Clostridium difficile infection outbreaks, unit-wide screening of 114 patients led to detection and isolation of 15 (13%) C. difficile asymptomatic carriers. Carriage prevalence varied between outbreaks, from 0% to 29% (P = .004). Isolating carriers was not associated with significantly shorter outbreak durations, compared with historical controls.

Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).

A panel of experts was convened by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) to update the 2010 clinical practice guideline on Clostridium difficile infection (CDI) in adults. The update, which has incorporated recommendations for children (following the adult recommendations for epidemiology, diagnosis, and treatment), includes significant changes in the management of this infection and reflects the evolving controversy over best methods for diagnosis. Clostridium difficile remains the most important cause of healthcare-associated diarrhea and has become the most commonly identified cause of healthcare-associated infection in adults in the United States. Moreover, C. difficile has established itself as an important community pathogen. Although the prevalence of the epidemic and virulent ribotype 027 strain has declined markedly along with overall CDI rates in parts of Europe, it remains one of the most commonly identified strains in the United States where it causes a sizable minority of CDIs, especially healthcare-associated CDIs. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, infection prevention, and environmental management.

Understanding Clostridium difficile Colonization.

Clostridium difficile is the main causative agent of antibiotic-associated and health care-associated infective diarrhea. Recently, there has been growing interest in alternative sources of C. difficile other than patients with Clostridium difficile infection (CDI) and the hospital environment. Notably, the role of C. difficile-colonized patients as a possible source of transmission has received attention. In this review, we present a comprehensive overview of the current understanding of C. difficile colonization. Findings from gut microbiota studies yield more insights into determinants that are important for acquiring or resisting colonization and progression to CDI. In discussions on the prevalence of C. difficile colonization among populations and its associated risk factors, colonized patients at hospital admission merit more attention, as findings from the literature have pointed to their role in both health care-associated transmission of C. difficile and a higher risk of progression to CDI once admitted. C. difficile colonization among patients at admission may have clinical implications, although further research is needed to identify if interventions are beneficial for preventing transmission or overcoming progression to CDI.