Plasmid genomic epidemiology of blaKPC carbapenemase-producing Enterobacterales in Canada, 2010-2021.

Carbapenems are considered last-resort antibiotics for the treatment of infections caused by multidrug-resistant Enterobacterales, but carbapenem resistance due to acquisition of carbapenemase genes is a growing threat that has been reported worldwide. Klebsiella pneumoniae carbapenemase (blaKPC) is the most common type of carbapenemase in Canada and elsewhere; it can hydrolyze penicillins, cephalosporins, aztreonam, and carbapenems and is frequently found on mobile plasmids in the Tn4401 transposon. This means that alongside clonal expansion, blaKPC can disseminate through plasmid- and transposon-mediated horizontal gene transfer. We applied whole genome sequencing to characterize the molecular epidemiology of 829 blaKPC carbapenemase-producing isolates collected by the Canadian Nosocomial Infection Surveillance Program from 2010 to 2021. Using a combination of short-read and long-read sequencing, we obtained 202 complete and circular blaKPC-encoding plasmids. Using MOB-suite, 10 major plasmid clusters were identified from this data set which represented 87% (175/202) of the Canadian blaKPC-encoding plasmids. We further estimated the genomic location of incomplete blaKPC-encoding contigs and predicted a plasmid cluster for 95% (603/635) of these. We identified different patterns of carbapenemase mobilization across Canada related to different plasmid clusters, including clonal transmission of IncF-type plasmids (108/829, 13%) in K. pneumoniae clonal complex 258 and novel repE(pEh60-7) plasmids (44/829, 5%) in Enterobacter hormaechei ST316, and horizontal transmission of IncL/M (142/829, 17%) and IncN-type plasmids (149/829, 18%) across multiple genera. Our findings highlight the diversity of blaKPC genomic loci and indicate that multiple, distinct plasmid clusters have contributed to blaKPC spread and persistence in Canada.

Effect of faecal microbial transplant via colonoscopy in patients with severe obesity and insulin resistance: A randomized double-blind, placebo-controlled Phase 2 trial.

AIM: To assess the effects of faecal microbial transplant (FMT) from lean people to subjects with obesity via colonoscopy. MATERIAL AND METHODS: In a double-blind, randomized controlled trial, subjects with a body mass index ≥ 35 kg/m2 and insulin resistance were randomized, in a 1:1 ratio in blocks of four, to either allogenic (from healthy lean donor; n = 15) or autologous FMT (their own stool; n = 13) delivered in the caecum and were followed for 3 months. The main outcome was homeostatic model assessment of insulin resistance (HOMA-IR) and secondary outcomes were glycated haemoglobin levels, lipid profile, weight, gut hormones, endotoxin, appetite measures, intestinal microbiome (IM), metagenome, serum/faecal metabolites, quality of life, anxiety and depression scores. RESULTS: In the allogenic versus autologous groups, HOMA-IR and clinical variables did not change significantly, but IM and metabolites changed favourably (P < 0.05): at 1 month, Coprococcus, Bifidobacterium, Bacteroides and Roseburia increased, and Streptococcus decreased; at 3 months, Bacteroides and Blautia increased. Several species also changed significantly. For metabolites, at 1 month, serum kynurenine decreased and faecal indole acetic acid and butenylcarnitine increased, while at 3 months, serum isoleucine, leucine, decenoylcarnitine and faecal phenylacetic acid decreased. Metagenomic pathway representations and network analyses assessing relationships with clinical variables, metabolites and IM were significantly enhanced in the allogenic versus autologous groups. LDL and appetite measures improved in the allogenic (P < 0.05) but not in the autologous group. CONCLUSIONS: Overall, in those with obeisty, allogenic FMT via colonoscopy induced favourable changes in IM, metabolites, pathway representations and networks even though other metabolic variables did not change. LDL and appetite variables may also benefit.

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults, Canada, 2015-2019.

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015-2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015-2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.

Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial.

BACKGROUND: Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. METHODS: In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. RESULTS: The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. CONCLUSIONS: In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. CLINICAL TRIALS REGISTRATION: NCT01226992.

Leading teams while exhausted: Perspectives from healthcare epidemiology and beyond.

Mental fatigue and burnout are concerns for healthcare organizations, but their effects on leaders have not been thoroughly studied. Infectious diseases teams and leaders are at risk for mental fatigue and burnout due to the increased demands from the coronavirus disease 2019 (COVID-19) pandemic, additive effects of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) (omicron) and δ (delta) variant surges, and unique pre-existing pressures. No single intervention can reduce stress and burnout in healthcare workers. Work-hour limitations may have the biggest impact in physician burnout mitigation. Institutional and individual programs focused on mindfulness may improve well-being in the workplace. Leading during times of stress requires a multimodal approach and an understanding of goals and priorities. Greater awareness of burnout and fatigue across the healthcare spectrum and continued research are required to advance healthcare worker well-being.

Vancomycin-resistant Enterococcus sequence type 1478 spread across hospitals participating in the Canadian Nosocomial Infection Surveillance Program from 2013 to 2018.

OBJECTIVE: To analyze the spread of a novel sequence type (ST1478) of vancomycin-resistant Enterococcus faecium across Canadian hospitals. DESIGN: Retrospective chart review of patients identified as having ST1478 VRE bloodstream infection. SETTING: Canadian hospitals that participate in the Canadian Nosocomial Infection Surveillance Program (CNISP). METHODS: From 2013 to 2018, VRE bloodstream isolates collected from participating CNISP hospitals were sent to the National Microbiology Laboratory (NML). ST1478 isolates were identified using multilocus sequence typing, and whole-genome sequencing was performed. Patient characteristics and location data were collected for patients with ST1478 bloodstream infection (BSI). The sequence and patient location information were used to generate clusters of infections and assess for intrahospital and interhospital spread. RESULTS: ST1478 VRE BSI occurred predominantly in a small number of hospitals in central and western Canada. Within these hospitals, infections were clustered on certain wards, and isolates often had <20 single-nucleotide variants (SNV) differences from one another, suggesting a large component of intrahospital spread. Furthermore, some patients with bloodstream infections were identified as moving from one hospital to another, potentially having led to interhospital spread. Genomic analysis of all isolates revealed close relatedness between isolates at multiple different hospitals (<20 SNV) not predicted from our epidemiologic data. CONCLUSIONS: Both intrahospital and regional interhospital spread have contributed to the emergence of VRE ST1478 infections across Canada. Whole-genome sequencing provides evidence of spread that might be missed with epidemiologic investigation alone.

Bloodstream infection and ventilator-associated pneumonia in patients with coronavirus disease 2019 (COVID-19) supported by extracorporeal membrane oxygenation.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) has been widely used in the care of patients with respiratory failure from coronavirus disease 2019 (COVID-19). We characterized bloodstream infections (BSIs) and ventilator-associated pneumonias (VAPs) in COVID-19 patients supported with ECMO, and we investigated their impact on patient outcomes. DESIGN: Retrospective cohort study from March 1, 2020, to June 30, 2021. SETTING: Academic tertiary-care referral center. PATIENTS: Consecutive adult patients admitted for COVID-19 who received ECMO. METHODS: We identified BSIs and VAPs and described their epidemiology and microbiology. Cumulative antimicrobial use and the specific management of BSIs were determined. Multivariate time-dependent Cox proportional hazards models were constructed to evaluate the impact of BSIs and VAPs on mortality, controlling for age, receipt of COVID-19-specific therapeutics, and new renal replacement therapy. RESULTS: We identified 136 patients who received ECMO for COVID-19 pneumonia during the study period. BSIs and VAPs occurred in 81 patients (59.6%) and 93 patients (68.4%), respectively. The incidence of BSIs was 29.5 per 1,000 ECMO days and increased with duration of ECMO cannulation. Enterococci, Enterobacterales, and Staphylococcus aureus were the most common causes of BSIs, whereas S. aureus, Klebsiella species, and Pseudomonas aeruginosa comprised the majority of VAPs. Mean antibiotic use comprised 1,031 days of therapy per 1,000 ECMO days (SD, 496). We did not detect an association between BSIs or VAPs and mortality. CONCLUSIONS: BSIs and VAPs are common in COVID-19 ECMO-supported patients. Efforts to optimize their diagnosis, prevention, and management should be prioritized.

Characterizing burnout among healthcare epidemiologists in the early phases of the COVID-19 pandemic: A study of the SHEA Research Network.

A multisite research team proposed a survey to assess burnout among healthcare epidemiologists. Anonymous surveys were disseminated to eligible staff at SRN facilities. Half of the respondents were experiencing burnout. Staffing shortages were a key stressor. Allowing healthcare epidemiologists to provide guidance without directly enforcing policies may improve burnout.

Epidemiology of Primary and Recurrent Healthcare-Associated and Community-Associated Pediatric Clostridioides difficile Infection in Canada, 2015-2020.

Clostridioides difficile infection (CDI) among children remains a concerning cause of morbidity in hospital settings. We present epidemiological and molecular trends in healthcare- and community-associated CDI among children in Canadian inpatient and outpatient settings, including those who experienced recurrent infections.

Gut microbiome modified by bariatric surgery improves insulin sensitivity and correlates with increased brown fat activity and energy expenditure.

Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice. Mice colonized by FMT from patients' post-surgery stool exhibit significant changes in microbiota composition and metabolomic profiles and, most importantly, improved insulin sensitivity compared with pre-RYGB FMT mice. Mechanistically, mice harboring the post-RYGB microbiome show increased brown fat mass and activity and exhibit increased energy expenditure. Moreover, improvements in immune homeostasis within the white adipose tissue are also observed. Altogether, these findings point to a direct role for the gut microbiome in mediating improved metabolic health post-RYGB surgery.

Trends in Clostridioides difficile infection rates in Canadian hospitals during the coronavirus disease 2019 (COVID-19) pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has placed significant burden on healthcare systems. We compared Clostridioides difficile infection (CDI) epidemiology before and during the pandemic across 71 hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Using an interrupted time series analysis, we showed that CDI rates significantly increased during the COVID-19 pandemic.

Determining mortality rates attributable to Clostridium difficile infection.

To determine accuracy of measures of deaths attributable to Clostridium difficile infection, we compared 3 measures for 2007-2008 in Ontario, Canada: death certificate; death within 30 days of infection; and panel review. Data on death within 30 days were more feasible than panel review and more accurate than death certificate data.

Out of sight, out of mind: a prospective observational study to estimate the duration of the Hawthorne effect on hand hygiene events.

BACKGROUND: Human auditing has been the gold standard for evaluating hand hygiene (HH) compliance but is subject to the Hawthorne effect (HE), the change in subjects' behaviour due to their awareness of being observed. For the first time, we used electronic HH monitoring to characterise the duration of the HE on HH events after human auditors have left the ward. METHODS: Observations were prospectively conducted on two transplant wards at a tertiary centre between May 2018 and January 2019. HH events were measured using the electronic GOJO Smartlink Activity Monitoring System located throughout the ward. Non-covert human auditing was conducted in 1-hour intervals at random locations on both wards on varying days of the week. Two adjusted negative binomial regression models were fit in order to estimate an overall auditor effect and a graded auditor effect. RESULTS: In total, 365 674 HH dispensing events were observed out of a possible 911 791 opportunities. In the adjusted model, the presence of an auditor increased electronic HH events by approximately 2.5-fold in the room closest to where the auditor was standing (9.86 events per hour/3.98 events per hour; p<0.01), an effect sustained across only the partial hour before and after the auditor was present but not beyond the first hour after the auditor left. This effect persisted but was attenuated in areas distal from the auditor (total ward events of 6.91*6.32-7.55, p<0.01). Additionally, there was significant variability in the magnitude of the HE based on temporal and geographic distribution of audits. CONCLUSION: The HE on HH events appears to last for a limited time on inpatient wards and is highly dynamic across time and auditor location. These findings further challenge the validity and value of human auditing and support the need for alternative and complementary monitoring methods.

Ethical implications of recruiting universal stool donors for faecal microbiota transplantation.

Faecal microbiota transplantation is an effective therapy for recurrent Clostridioides difficile infection, with potential therapeutic applications in other health conditions. As research uncovers potential associations between the intestinal microbiome and various disease states, stool donor screening has become increasingly stringent, leading to low donor acceptance. Many stool banks have opted to recruit universal stool donors, who are encouraged to donate frequently over a prolonged period and whose stool is used to treat multiple patients. However, various ethical concerns arise when recruiting universal stool donors, which need to be addressed to mitigate harm to donors. In this Personal View, we describe the major ethical issues with universal stool banks across six domains: informed consent, privacy, the imposing of restrictions on autonomy, stewardship of microbiome information, financial incentives, and preventing a sense of obligation. We also suggest several priorities for future research that should be pursued to address these crucial issues and develop more donor-centric stool banks.

Challenges establishing a multi-purpose fecal microbiota transplantation stool donor program in Toronto, Canada.

Background: The success of fecal microbiota transplantation (FMT) programs depends on maintaining suitable stool donors. We describe challenges recruiting and retaining universal donors in the first 2 years of an FMT clinical and research program in Toronto and identify opportunities for improvement. Methods: A four-stage screening process is used to identify suitable FMT donors in the Microbiota Therapeutics Outcomes Program. Donor screening follows Health Canada recommendations and excludes persons with history or risk for diseases associated with dysbiosis. Donors are rescreened microbiologically approximately every 1-3 months and answer ongoing health, exposure, and dietary questionnaires. Results: In the first 2 years of our program, 5 of 322 (1.6%) prospective stool donors passed initial screening, and only 2 (0.6%) were retained. Most prospective donors were excluded on telephone screening, at which point high BMI, medication use, and family history of relevant illness were common exclusions. No candidate was excluded because of a concerning physical examination. Microbiologic reasons for donor exclusion included carriage of Blastocystis hominis (n = 2), Helicobacter pylori (n = 2), extended spectrum beta-lactamase producing organisms (n = 1), Shiga-toxin producing Escherichia coli (n = 1), and sapovirus (n = 1). Universal donors were lost temporarily because of travel, antibiotic exposures, and transient carriage of antibiotic-resistant organisms. Conclusions: Recruiting and retaining suitable donors for FMT is challenging because of rigorous exclusions and labour-intensive screening processes. We present considerations for efficiency in donor screening, including targeting recruitment populations, expanded website self-screening, eliminating physical examinations, and streamlining post-travel risk assessment.

Historique: Le succès des programmes de transplantation de microbiote fécal (TMF) dépend de la rétention de donneurs fécaux appropriés. Les auteurs décrivent les difficultés à recruter et à conserver des donneurs universels dans les deux premières années d'un programme clinique et de recherche de TMF à Toronto ainsi qu'à déterminer les possibilités d'amélioration. Méthodologie: Un processus de sélection en quatre étapes permet de déterminer les donneurs de TMF appropriés au sein du programme de résultats thérapeutiques du microbiote. La sélection des donneurs suit les recommandations de Santé Canada et exclut les personnes ayant des antécédents ou un risque de maladies associés à la dysbiose. Les donneurs reprennent une sélection microbiologique environ tous les un à trois mois et répondent à des questionnaires sur la santé, l'exposition et le régime alimentaire. Résultats: Au cours de deux premières années du programme, cinq des 322 donneurs prospectifs de matière fécale (1,6 %) ont réussi la sélection initiale, et seulement deux (0,6 %) ont été retenus. La plupart des donneurs prospectifs ont été exclus à la sélection téléphonique; un IMC élevé, la prise de médicaments et des antécédents familiaux de maladie pertinente étaient des exclusions courantes. Aucun candidat n'a été exclu à cause d'un examen physique inquiétant. Les raisons microbiologiques d'exclure les donneurs incluaient le portage de Blastocystis hominis (n = 2), d'Helicobacter pylori (n = 2), d'organismes producteurs de bêta-lactamase à large spectre (n = 1), d'Escherichia coli producteur de la toxine de Shiga (n = 1) et du sapovirus (n = 1). Des donneurs temporaires étaient perdus temporairement à cause de voyages, d'exposition à des antibiotiques et de portage transitoire d'organismes antibiorésistants. Conclusions: Il est difficile de recruter et de retenir des donneurs appropriés de TMF en raison des exclusions rigoureuses et des processus de dépistage fastidieux. Les auteurs présentent des considérations d'efficacité pour le dépistage des donneurs, y compris le ciblage de populations à recruter, l'autodépistage élargi dans les sites Web, l'élimination des examens physiques et la rationalisation de l'évaluation du risque après le voyage.