Healthcare-associated infections and antimicrobial resistance in Canadian acute care hospitals, 2018–2022

Background Healthcare-associated infections (HAIs) and antimicrobial resistance (AMR) continue to contribute to excess morbidity and mortality among Canadians. Objective This report describes epidemiologic and laboratory characteristics and trends of HAIs and AMR from 2018 to 2022 (Candida auris, 2012–2022) using surveillance and laboratory data submitted by hospitals to the Canadian Nosocomial Infection Surveillance Program (CNISP) and by provincial and territorial laboratories to the National Microbiology Laboratory. Methods Data collected from 88 Canadian sentinel acute care hospitals between January 1, 2018, and December 31, 2022, for Clostridioides difficile infections (CDIs), carbapenemase-producing Enterobacterales (CPE) infections, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) and vancomycin-resistant Enterococcus (VRE) BSIs. Candida auris (C. auris) surveillance was initiated in 2019 by CNISP and in 2017 (retrospectively to 2012) by the National Microbiology Laboratory. Trend analysis for case counts, rates, outcomes, molecular characterization and AMR profiles are presented. Results From 2018 to 2022, decreased rates per 10,000 patient days were observed for CDIs (7% decrease; 5.42–5.02) and MRSA BSIs (2.9% decrease; 1.04–1.01). Infection rates for VRE BSIs increased by 5.9% (0.34–0.36). Infection rates for CPE remained low but increased by 133% (0.06–0.14). Forty-three C. auris isolates were identified in Canada from 2012 to 2022, with the majority in Western and Central Canada (98%). Conclusion From 2018 to 2022, the incidence of MRSA BSIs and CDIs decreased and VRE BSI and CPE infections increased in the Canadian acute care hospitals participating in a national sentinel network (CNISP). Few C. auris isolates were identified from 2012 to 2022. Reporting standardized surveillance data to inform the application of infection prevention and control practices in acute care hospitals is critical to help decrease the burden of HAIs and AMR in Canada.


Introduction
Healthcare-associated infections (HAI) represent one of the most common adverse events experienced by patients in acute care settings globally (1).In addition to increasing morbidity and mortality, they are associated with longer lengths of stay (LOS) in hospitals and higher costs of care.The prevalence of HAIs has been estimated to be at 3.2% in the United States (US), 6.5% in Europe and 9.9% in Australia, and is likely two-fold greater in developing countries (1)(2)(3)(4).In Europe, the cumulative healthcare burden of six HAIs (urinary tract infection, pneumonia, surgical site infection, Clostridioides difficile infections [CDIs], bloodstream infections [BSIs], and neonatal sepsis) was greater than the burden of 32 other communicable diseases combined, including influenza and tuberculosis (5).In Canada, a point prevalence survey conducted in 2017 estimated that the prevalence of patients with at least one HAI was 7.9% (6).Importantly, a large proportion of HAIs are preventable and evidence from the US shows that advancements in care and infection prevention and control can decrease HAI rates over time (2).
Many of the microorganisms that cause HAIs have a propensity for antimicrobial resistance (AMR), and growing rates of resistance threaten to undermine efforts to reduce HAI rates (5).Infection with a resistant organism is associated with an 84.4% increased risk of death and in 2019, bacterial AMR was associated with approximately five million deaths globally (7,8).The global economic costs of AMR are also significant (8).Canadian data show that CDI is associated with a longer length of hospital stay, higher all-cause mortality and an average excess cost of $11,056 per patient (9).The rate of AMR is predicted to reach 40% by 2050.In this situation, it is forecasted that 13,700 Canadians could die each year from resistant infections, and the overall annual impact to Canada's GDP would be $21 billion (10).Inappropriate antimicrobial use during the recent COVID-19 pandemic may have contributed towards an increase in AMR (11).Moreover, emerging resistant pathogens such as Candida auris (C.auris) have necessitated enhanced surveillance and changes to existing infection prevention and control protocols (12).Coordinated global public health action, surveillance, improved antibiotic stewardship, infection prevention and control and public awareness are crucial to identify patterns of antimicrobial resistance and prevent and control emerging infections.
In Canada, the Public Health Agency of Canada collects national data on various HAIs and AMR through the Canadian Nosocomial Infection Surveillance Program (CNISP).Established in 1994, CNISP is a collaboration between the Public Health Agency of Canada, the Association of Medical Microbiology and Infectious Disease Canada and sentinel hospitals from across Canada.The goal of CNISP is to facilitate and inform the prevention, control and reduction of HAIs and antimicrobial resistant organisms in Canadian acute care hospitals through active surveillance and reporting.
In line with the World Health Organization's core components of infection prevention and control (13), CNISP performs consistent, standardized surveillance to reliably estimate HAI burden, establish benchmark rates for national and international comparison, identify potential risk factors and assess and inform specific interventions to improve patient health outcomes.Data provided by CNISP directly support the collaborative goals outlined in the Pan-Canadian Action Plan on Antimicrobial Resistance (14).
In this report, we describe the most recent HAI and AMR surveillance data collected from CNISP participating hospitals between 2018 and 2022.Further, we provide a summary of C. auris isolates identified from 2012 to 2022 to describe the epidemiology of this pathogen in Canada.

Case definitions
Standardized case definitions for healthcare-associated (HA) and community-associated (CA) infections were used.Refer to Appendix A for full-case definitions.

Data sources
Between January 1, 2018, and December 31, 2022, participating hospitals submitted epidemiologic data and isolates for cases meeting the respective case definitions for CDI, methicillinresistant Staphylococcus aureus (MRSA) BSIs, vancomycinresistant Enterococcus (VRE) BSIs and carbapenemase-producing Enterobacterales (CPE) infections.Eligible C. auris isolates (infections or colonizations) were identified by provincial and territorial laboratories and participating hospital laboratories between January 1, 2012, and December 31, 2022, while CNISP surveillance for clinical characteristics of C. auris began on January 1, 2019.In 2022, 88 hospitals in 10 provinces and one territory participated in HAI surveillance and are further described in Table 1 and Appendix B, Supplemental Figure S1.Hospital participation varied by surveillance project and year.In 2022, patient admissions captured in CNISP HAI surveillance were distributed across hospitals categorized as either small (1-200 beds, n=39 sites, 44%), medium (201-499 beds, n=34 sites, 39%) or large (500 or more beds, n=15 sites, 17%) (Table 1).Reviews of standardized protocols and case definitions are conducted annually by established infectious disease expert working groups; training for data submission is provided to participating CNISP hospital staff as required.Data quality for surveillance projects is periodically evaluated; additional details on the methodology have been published previously (16,17).

Statistical analysis
Rates of HAI were calculated by dividing the total number of cases identified in patients admitted to CNISP participating hospitals by the total number of patient admissions (multiplied by 1,000) or patient days (multiplied by 10,000).The HAI rates are reported nationally and by region as shown in Table 1.Sites that were unable to provide case data were excluded from rate calculations and missing denominator data were estimated using their previous years reported data, where applicable.Missing epidemiological and molecular data were excluded from analysis.The Mann-Kendall test was used to test trends.Significance testing was two-tailed and differences were considered significant at p≤0.05.
Where available, attributable and all-cause mortality were reported for HAIs.Attributable mortality rate was defined as the number of deaths per 100 HAI cases where the HAI was the direct cause of death or contributed to death within 30 days of positive culture or histopathology specimen, as determined by physician review.All-cause mortality rate was defined as the number of deaths per 100 HAI cases 30 days following positive culture.

Carbapenemase-producing Enterobacterales
From 2018 to 2022, CPE infection rates have remained low, although there has been a non-significant increase of 133% in the rates over this period (0.06 to 0.14 infections per 10,000 patient days, p=0.07) (Table 5).
From  S4.2).Among the predominant cabapenemases, from 2019 to 2022, the prevalence of meropenem resistance among K. pneumoniae carbapenemase isolates decreased by 13.3%.Among New Delhi metallo-β-lactamase isolates, the prevalence of aztreonam resistance decreased by 13%, while amikacin resistance increased by 10.8%.Among OXA-48 isolates, the largest decreases in resistance were seen in ceftriaxone, tobramycin and trimethorpim/sulfamethoxazole (26.6%, 22.5% and 22.3%, respectively) (Appendix B, Table S4.3 to S4.5).Declining CDI rate trends observed in the CNISP network follow a parallel trend observed globally; however, rates have been reported to be higher in North America (18,19).German hospitals have seen an approximate 50% decrease in CDI cases from 2015 to 2021 (20).Enhanced infection control practices, antimicrobial stewardship measures and improved surveillance and detection methods may have contributed to the overall decline seen in CDI rates (19).Additionally, CA-CDI patients with mild to moderate symptoms might not have any interactions with the healthcare system, resulting in underestimation of the true burden of CA-CDI (19).

Candida auris
In a representative sample of Canadian acute care hospitals, from 2018 to 2022, a 3.8% decrease in moxifloxacin resistance in both HA and CA-CDI populations is concordant with an overall decrease in the prevalence of RT027.Furthermore, moxifloxacin resistance remained lower (7.3% in 2022) than previously published weighted pooled resistance data for North America (44.0%) and Asia (33.0%) (21,22).The decline in RT027 prevalence from 2018 to 2022 may also have influenced the decline in CDI rates among CNISP hospitals as this ribotype has been associated with increased virulence and fluoroquinolone resistance (23).Additionally, the emergence of RT106 found worldwide and most predominantly in the US presents more fluoroquinolone resistance and higher recurrence rates.The potential emergence of resistant ribotypes warrants further surveillance, monitoring and investigation (24,25).Vancomycin resistance related to VRE BSI has been shown to be a principal predictor of mortality and is associated with increased hospital burden (37)(38)(39).The VRE BSI rate observed in the CNISP network was highest in 2022 (0.36 infections per 10,000 patient days).The ST17 sequence type has contributed to the increased burden of VRE BSI in CNISP-participating hospitals by emerging as the predominant clone, overtaking ST1478.An increase in ST80 has also been seen in CNISP data, increasing from 11.7% in 2018 to 30.6% in 2022.The increase in ST80 seen in Canada is consistent with what has been observed in Sweden over the last three years, resulting in vanA-type and vanB-type outbreaks (40).The VRE BSI trends are further impacted by the number of high-risk patients admitted to hospital (e.g., bone marrow transplants, solid organ transplants, cancer patients, etc.) (41).Although there is a lack of recent data on VRE BSI rates in comparable jurisdictions, there have been increasing trends noted in Europe (42)(43)(44)(45), which may be associated, in part, with the introduction and spread of new clones and gaps in infection prevention practices (44)(45)(46).
Carbapenemase-producing Enterobacterales infections are a significant threat to public health as they are becoming increasingly prevalent in healthcare environments worldwide (47).
Active infection with CPE carries a high mortality rate, with the bacteria being resistant to many antibiotics, limiting treatment options for these patients (5,(48)(49)(50)(51)(52).The Centers for Disease Control and Prevention and the World Health Organization have classified CPE as one of the most urgent antimicrobialresistance threats (52,53).While the number of CPE infections increased from 2018 to 2022 in the CNISP network, incidence remained low (54).Data on the incidence of CPE infections in other countries, such as the United Kingdom, have also shown an increasing incidence of CPE infections (54,55).Similarly, the number of CPE isolates identified through laboratory surveillance associated with CPE infections has increased in Switzerland from 2013 to 2018 (56).More recently, a shift in the acquisition source of CPE has been observed within the CNISP network.Previously, CPE infections were mostly associated with international travel, but have recently become acquired domestically (85.3%) from 2020 to 2022.As a result, strict implementation of infection control measures, including screening in patients with a previous hospital admission domestically and abroad, are useful to reduce the transmission of CPE in Canadian acute care hospitals.
Candida auris is an emerging multi-drug resistant fungus that can cause HA invasive infections and outbreaks (57).It has been detected across multiple countries and continents including Canada, since its first detection in 2009 (58)(59)(60)(61).
Candida auris has been associated with outbreaks in healthcare settings in many countries, including Canada and the US, although outbreaks in Canada to date have been limited with few cases (57).Reported crude mortality for C. auris ranges widely from 15%-60% but is generally similar to other Candida species (57)(58)(59)(60)(61)(62)(63).Though still relatively rare in Canada, the US reported over 2,000 clinical cases and over 5,000 screening cases in 2022 (64).A survey examining C. auris preparedness within CNISP hospitals in 2018 found that most hospitals did not yet have laboratory protocols or infection prevention and control policies in place for detecting and controlling C. auris (65).The identification of C. auris in routine microbiology laboratories requires identification of Candida to the species level, which may not be routinely performed for isolates from non-sterile sites.Treatment options are limited for patients as one third of identified C. auris isolates in Canada were multidrug-resistant and additional resistance can develop during antifungal therapy (66).Therefore, rapid identification, screening for colonization in at-risk patients and strict implementation of infection prevention and control measures are required to reduce the transmission of C. auris in Canadian healthcare settings.Continued reporting on C. auris in Canada is important to assess and monitor the risk of this pathogen, in addition to identifying epidemiological and microbiological trends (66).
The COVID-19 pandemic has had a varied effect on the rates of HAIs in Canada and in the US (67,68).When looking at HAI rates before and during the COVID-19 pandemic, the data showed an immediate increase in HA rates of CDI while MRSA BSI, CPE infection and VRE BSI rates immediately decreased; however, COVID-19 pandemic status was not associated with lasting impacts on monthly rate trends in these infections (69).

SURVEILLANCE
Pandemic-related improvements in hand hygiene, personal protective equipment practices, environmental cleaning, screening and infection control practices may have contributed to the decreases in rates observed over the reporting period (70).

Strengths and limitations
The main strength of CNISP is the collection of standardized and detailed epidemiological and laboratory-linked data from 88 sentinel hospitals across Canada for the purpose of providing national HAI and AMR trends for benchmarking and to inform hospital infection prevention and control practices.It is important to note that data in this report include those from the early years of the COVID-19 pandemic; therefore, rates of HAIs and AMR in 2020 and 2021 may be impacted by changes in national, regional and municipal hospital-based infection prevention and control measures.
Epidemiological data collected by CNISP were limited to information available in patient charts.

SURVEILLANCE
Healthcare-associated CDI but unable to determine which facility: The patient with CDI DOES meet both definitions of healthcareassociated (acquired in your facility) and healthcare-associated (acquired in any other healthcare facility) CDI, but unable to determine to which facility the case is primarily attributable to.
Community-associated CDI case definition: • Inpatient: the patient's CDI symptoms occur less than three days (or fewer than 72 hours) after admission, with no history of hospitalization or any other healthcare exposure within the previous 12 weeks • Outpatient: the patient presents with CDI symptoms at your ER or outpatient location with no history of hospitalization or any other healthcare exposure within the previous 12 weeks Indeterminate CDI case definition: The patient with CDI does NOT meet any of the definitions listed above for healthcare-associated or community-associated CDI.
The symptom onset was more than four weeks but fewer than 12 weeks after the patient was discharged from any healthcare facility or after the patient had any other healthcare exposure.

SURVEILLANCE
• In the case of a newborn transferred from another institution, MSSA or MRSA BSI may be classified as HA your acute-care facility if the organism was NOT known to be present and there is no epidemiological reason to suspect that acquisition occurred prior to transfer Community-associated case definition: • No exposure to healthcare that would have resulted in this bacteremia (using best clinical judgment) and does not meet the criteria for a healthcare-associated BSI

Vancomycin-resistant Enterococcus (VRE) infection
VRE BSI case definition: A newly identified VRE BSI is defined as a positive VRE blood isolate more than 14 days after completion of therapy for a previous infection and felt to be unrelated to previous infection in accordance with best clinical judgment by infection control physicians and practitioners.
Exclusion criteria: • Emergency, clinic, or other outpatient cases who are not admitted to the hospital Healthcare-associated (HA) case definition: Healthcare-associated is defined as an inpatient who meets the following criteria and in accordance with the best clinical judgment of the healthcare and/or infection prevention and control practitioner: • Patient is on or beyond calendar day 3 of their hospitalization (calendar day 1 is the day of hospital admission)

OR
• Has been hospitalized in your facility in the last 7 days or up to 90 days depending on the source of the infection OR • Has had a healthcare exposure at your facility that would have resulted in this bacteremia (using best clinical judgment)

OR
• Any patient who has a bacteremia not acquired at your facility that is thought to be associated with any other healthcare exposure (e.g., another acute-care facility, longterm care, rehabilitation facility, clinic or exposure to a medical device)

Carbapenemase-producing Enterobacterales (CPE) infection
Case eligibility: • Patient is admitted to a CNISP hospital or presents to a CNISP hospital emergency department or a CNISP hospitalbased outpatient clinic • Laboratory confirmation of carbapenem resistance or carbapenemase production in Enterobacterales spp.
Following molecular testing, only isolates determined to be harbouring a carbapenemase are included in surveillance.If multiple isolates are submitted for the same patient in the same surveillance year, only the isolate from the most invasive site is included in epidemiological results (e.g., rates and outcome data).However, antimicrobial susceptibility testing results represent all CPE isolates (including clinical and screening isolates from inpatients and outpatients) submitted between 2018 and 2022; duplicates (i.e., isolates from the same patient where the organism and the carbapenemase were the same) were excluded.

Candida auris
Patients admitted to a participating hospital or presenting to a hospital emergency department or a hospital-based outpatient clinic with laboratory confirmation of C. auris from any specimen.
Included in this surveillance project are all clinical or screening samples that were positive for C. auris by any method.Currently, C. auris can be identified by rRNA sequencing, Vitek MS MALDI-TOF (with either the clinical database v3.2 or later or the RUO database), or Bruker MALDI-TOF (with either the clinical database v6903 or later or the RUO database).The project also includes potential C. auris misidentifications or "No identification" as outlined in the Table A1 below.
Isolation of Enterococcus faecalis or faecium from blood AND • Vancomycin minimum inhibitory concentration (MIC) of at least 8 µg/ml AND • Patient must be admitted to the hospital AND • Is a "newly" identified VRE BSI at a CNISP facility at the time of hospital admission or identified during hospitalization

Table 1 :
Summary of hospitals participating in the Canadian Nosocomial Infection Surveillance Program, by region, 2022 a Western refers to British Columbia, Alberta, Saskatchewan and Manitoba b Central refers to Ontario and Québec c Eastern refers to Nova Scotia, New Brunswick, Prince Edward Island and Newfoundland and Labrador d Northern refers to Yukon, Northwest Territories and Nunavut e Eleven hospitals classified as "adult" had a neonatal intensive care unit Epidemiologic (demographic, clinical and outcomes) and denominator data (patient days and patient admissions) were collected and submitted by participating hospitals through the Canadian Network for Public Health Intelligence, a secure online data platform.

Table 2 :
Clostridioides difficile infection data, Canada, 2018-2022 a Abbreviations: C. difficile, Clostridioides difficile; N/A, not applicable a All C. difficile isolates from 2017 to 2021 submitted to the National Microbiology Laboratory were susceptible to tigecycline and vancomycin b Deaths where C. difficile infection was the direct cause of death or contributed to death 30 days after the date of the first positive lab specimen or positive histopathology specimen.Mortality data are collected during the two-month period (March and April of each year) for adults (aged 18 years and older) and year-round for children (aged one year to younger than 18 years old).Among paediatric patients, there was no death attributable to healthcare-associated C. difficile infection c C. difficile infection isolates are collected for resistance testing during the two-month period (March and April of each year) for adults (aged 18 years and older) and year-round for children (aged one year to younger than 18 years old) from admitted patients only d Total number reflects the number of isolates tested for each of the antibiotics listed aboveSURVEILLANCEBetween 2018 and 2022, the proportion of spa types identified as t002 (CMRSA2) and most commonly associated with HA-MRSA continued to decrease from 25.3% of all HA-MRSA isolates in 2018 to 6.4% in 2022.The proportion of spa types identified as t008 (CMRSA10) and most commonly associated with CA-MRSA continued to increase and account for the largest proportion of CA-MRSA isolates from 45.0% in 2018 to 49.1% in 2022 (Appendix B, Table

Table 3 :
Methicillin-resistant Staphylococcus aureus bloodstream infections data, Canada, 2018-2022 Abbreviations: MRSA BSI, methicillin-resistant Staphylococcus aureus bloodstream infection; N/A, not applicable a Based on the number of cases with associated 30-day outcome data b All MRSA isolates from 2018 to 2022 submitted to the National Microbiology Laboratory were susceptible to linezolid, nitrofurantoin and vancomycin c In some years, the number of isolates tested for resistance varied by antibiotic d Total number reflects the number of isolates tested for each of the antibiotics listed above

Table 4 :
Vancomycin-resistant Enterococcus faecium bloodstream infections data, 2018-2022 Abbreviations: N/A, not applicable; VRE BSI, vancomycin-resistant Enterococcus bloodstream infection a Clinical and Laboratory Standards Institute (CLSI) resistance breakpoints came into effect in 2019 and was applied to all years b Total number reflects the number of isolates tested for each of the antibiotics listed above Note: Aggregate mortality data reported in-text due to fluctuations in the small numbers of VRE BSI deaths reported each year

table Note :
(26)(27)(28)(29)ity data reported in-text due to fluctuations in the small numbers of CPE deaths reported each year From 2018 to 2022, MRSA BSI rates decreased overall by 2.9% in the CNISP network.Although for three years, from 2019 to 2021, rates peaked at 1.13-1.16infectionsper10,000 patient days.Methicillin-resistant Staphylococcus aureus BSI is associated with increased morbidity and mortality, increased length of hospital stays and increased costs among admitted patients(26)(27)(28)(29).
ConclusionSurveillance findings from a national sentinel network of Canadian acute care hospitals indicate that rates of MRSA BSI and CDI have decreased from 2018 to 2022, while rates of VRE BSI and CPE infections have increased.Few cases of C. auris were detected in Canada from 2012 to 2022.Consistent and standardized surveillance of epidemiologic and laboratory HAI data are essential to providing hospital practitioners with benchmark rates and informing infection prevention and control and antimicrobial stewardship policies to help reduce the burden of HAI and the impact of AMR in Canadian acute care hospitals.