Healthcare-associated infections and antimicrobial resistance in Canadian acute care hospitals, 2017–2021

Background Healthcare-associated infections (HAIs) and antimicrobial resistance (AMR) continue to contribute to excess morbidity and mortality among Canadians. This report describes epidemiologic and laboratory characteristics and trends of HAIs and AMR from 2017 to 2021 (Candida auris 2012–2021) using surveillance and laboratory data submitted by hospitals to the Canadian Nosocomial Infection Surveillance Program (CNISP) and by provincial laboratories to the National Microbiology Laboratory (NML). Methods Data collected from 88 Canadian sentinel acute care hospitals between January 1, 2017, and December 31, 2021, for Clostridioides difficile infections (CDI), carbapenemase-producing Enterobacterales (CPE), 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 2012 by the NML. Case counts, rates, outcomes, molecular characterization and antimicrobial resistance profiles are presented. Results From 2017 to 2021, increased rates per 10,000 patient days were observed for MRSA BSIs (35%; 0.84–1.13), VRE BSIs (43%; 0.23–0.33) and CPE infections (166%, 0.03–0.08). CDI rates decreased 11% (5.68–5.05). Thirty-one C. auris isolates were identified in Canada from 2012 to 2021, with the majority from Western Canada (68%). Conclusion From 2017 to 2021, the incidence of MRSA and VRE BSIs, and CPE infections increased in Canadian acute care hospitals participating in a national sentinel network (CNISP) while CDI decreased. Few C. auris isolates were identified from 2012 to 2021. Reporting standardized surveillance data and the consistent application of infection prevention and control practises in acute care hospitals are critical to help decrease the burden of HAIs and AMR in Canada.


Introduction
Healthcare-associated infections (HAIs), including antimicrobial resistant organisms, continue to place a significant burden on the Canadian healthcare system, and cause excess morbidity and mortality (1)(2)(3)(4)(5).Point-prevalence studies conducted in Canada and across Europe in 2017 have estimated 6.5%-7.9% of patients in acute care facilities had at least one HAI (6,7).The United States Centers for Disease Control and Prevention estimated that one in 31 hospitalized patients were infected with an HAI, corresponding to 687,000 infections and 72,000 deaths each year (8).
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.
Reviews of standardized protocols and case definitions were conducted annually by established infectious disease expert working groups; training for data submission was provided to participating CNISP hospital staff as required.Data quality for surveillance projects was periodically evaluated; methodology has been published previously (15,16).

Laboratory data
Patient-linked laboratory isolates (stool samples for CDI cases) were sent to the Public Health Agency of Canada's National Microbiology Laboratory (NML) for molecular characterization and susceptibility testing.Isolates for MRSA BSI, VRE BSI, CPE, C. auris (2019-2021) and paediatric CDI were submitted yearround.Adult CDI isolates were submitted annually during a targeted two-month period (March 1 to April 30).Provincial laboratories have submitted C. auris isolates to NML since 2012.

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 (Western: British Columbia, Alberta, Saskatchewan and Manitoba; Central: Ontario and Québec; Eastern: Nova Scotia, New Brunswick, Prince Edward Island and Newfoundland and Labrador; Northern: Nunavut).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 2017 to 2021, CPE infection rates have remained low.A slight increase was observed from 2017 to 2018 (0.03 to 0.06 infections per 10,000 patient days, respectively) and rates have remained stable from 2018 to 2021 (Table 5).
From The COVID-19 pandemic has had a varied effect on the rates of HAIs in Canada and in the United States (13,17).Modelling HAI rates before and during the COVID-19 pandemic showed evidence of an immediate increase in HA rates of CDI while MRSA BSI, CPE and VRE BSI rates immediately decreased; however, COVID-19 pandemic status was not associated with lasting impacts on monthly rate trends in these infections (18).
Studies have suggested pandemic-related factors that may have contributed to the changes in observed rates of HAIs, such as public health measures implemented in both the hospital and the community, population travel and mobility, changes in infection control practises, screening, laboratory testing and antimicrobial stewardship (14).
Declining CDI rate trends observed in the CNISP network are like those reported globally; however, rates have been reported to be higher in North America than other regions (19).The overall reduction in CDI rates across Canada suggests improvements in infection prevention and control practises and qualityimprovement initiatives such as hand hygiene compliance, environmental cleaning, improved laboratory diagnostic techniques and antibiotic stewardship (20,21).In 2020, during the COVID-19 pandemic, there was evidence of an immediate increase in rates of CDI in the CNISP network, in contrast with the United States where rates continued to decline (17); however, the COVID-19 pandemic was not associated with a lasting impact on CDI rate trends.
In Canada, ribotype 027 continued to decrease in prevalence from 2017 to 2021, and coincided with a 7.8% decrease in moxifloxacin resistance during this time period.Furthermore, moxifloxacin resistance remained lower (9.1% in 2021) than previously published weighted pooled resistance data for North America (44.0%) and Asia (33.0%) (22,23).The decline in RT027 prevalence from 2017 to 2021 may also have influenced the decline in CDI rates among CNISP hospitals as this ribotype has been associated with increased virulence and fluoroquinolone resistance (24).
From 2017 to 2021, MRSA BSI rates continued to increase in the CNISP network, and is attributed to the increase in CA cases.Methicillin-resistant S. aureus BSI is associated with increased  (31).
The increasing number of patients identified with CA-MRSA who were admitted to hospital in the CNISP network may be associated with a growing CA-MRSA reservoir, both in Canada and globally (32,33).Increased rates of CA-MRSA BSI suggests that strategies that target the reduction and prevention of MRSA infections in the community, especially in populations with increased risk of contracting CA-MRSA (i.e.children, athletes, incarcerated populations, people who inject drugs), such as screening and eradication of the carriage of MRSA, may be effective in reducing the burden of MRSA BSI overall (34,35).
The increase in VRE BSI rates in Canadian acute care hospitals is concerning as vancomycin resistance related to this infection has been shown to be a principal predictor of mortality, and is associated with increased hospital burden (36)(37)(38).The increase in VRE BSI rates observed in the CNISP network may be linked to changes in infection control policies, including the discontinuation of VRE screening and isolation programs in some Canadian acute care hospitals (39).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.The ST17 sequence type is a globally disseminated VRE clone endemic in many countries but previously observed in low numbers in Canada (40).Changes in the resistance profiles of VRE BSI coincide with changes in ST distributions.The ST17 sequence type is associated with nitrofurantoin and chloramphenicol resistance, and the increase in ST17 prevalence corresponds to the increasing trend in resistance detected for these antimicrobials while daptomycin and high-level gentamicin resistance, associated with ST1478, have decreased since 2017.Vancomycin-resistant Enterococcus 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 a new clone and gaps in infection prevention practises (44)(45)(46).
Carbapenemase-producing Enterobacterales infections are a significant threat to public health due to their resistance to last line antimicrobials, limiting treatment options for patients with an infection due to pathogens that have the propensity to rapidly spread in healthcare settings (47)(48)(49)(50)(51).While the number of CPE infections increased from 2017 to 2021 in the CNISP network, incidence remained stable from 2018 to 2021.Data on the incidence of CPE infections in other countries, such as the United Kingdom, have noted increasing incidence of CPE infections (52,53).Similarly, the number of CPE isolates identified through laboratory surveillance associated with CPE infections has increased in Switzerland from 2013 to 2018 (54).Strict implementation of infection control measures, including screening for patient travel history, is essential to reduce the transmission of CPE in Canadian acute care hospitals.
Candida auris is an emerging multi-drug resistant fungus which has been detected across multiple countries and continents including Canada, since its first detection in 2009.Candida auris has been associated with outbreaks in healthcare settings in many countries, including Canada and the United States (55-58), and can cause both superficial and invasive infections with mortality ranging from 30%-60% (59).Though still relatively rare in Canada, the United States reported almost 8,000 clinical and screening cases in a recent one-year period (60).We evaluated C. auris preparedness within CNISP hospitals in 2018 and found that most hospitals did not yet have laboratory protocols or infection prevention and control policies in place for detecting and controlling C. auris (61).The identification of C. auris in routine microbiology laboratories requires identification of Candida to the species level, which may not be routinely performed due to challenges in balancing cost with value added for clinical decision-making.Treatment options are limited for patients as one third of identified C. auris isolates in Canada were multi-drug-resistant and additional resistance can develop during antifungal therapy (62).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 risk of this pathogen, in addition to identifying epidemiological and microbiological trends (63).

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 practises.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.Hospital staff turnover may affect the consistent application of CNISP definitions when reviewing medical charts; however, these data were collected by experienced and trained infection prevention and control staff who receive periodic training with respect to CNISP methods and definitions.Furthermore, data quality assessments were conducted to maintain and improve data quality.Recruitment efforts have increased representation and coverage of Canadian acute care beds in the CNISP network from 32% to 35% from 2017 to 2021, notably among northern, rural communities and Indigenous populations.

Next steps
Recruitment of Canadian acute care hospitals to the CNISP network in all ten provinces and three territories is an ongoing effort to improve the quality and representativeness of Canadian HAI surveillance data.Furthermore, the enhanced hospital screening practices survey is conducted annually to better understand and contextualize changes in HAI rates in the CNISP network.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), 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.

Methicillin-resistant Staphylococcus aureus (MRSA) infection
MRSA bloodstream infection (BSI) 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) Healthcare-associated (HA) case definition (newborn): • The newborn is on or beyond calendar day 3 of their hospitalization (calendar day 1 is the day of hospital admission) • The mother was NOT known to have MRSA on admission and there is no epidemiological reason to suspect that the mother was colonized prior to admission, even if the newborn is fewer than 48 hours of age • 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: • Isolation of Enterococcus faecalis or faecium from blood AND • Vancomycin MIC 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 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 2016 and 2020; 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.

Table 1 :
Summary of hospitals participating in the Canadian Nosocomial Infection Surveillance Program, by region, 2021 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 Nunavut e Seven hospitals classified as "adult" had a neonatal intensive care unit

Table 2 :
Clostridioides difficile infection data, Canada, 2017-2021 a 49breviations: C. difficile, Clostridioides difficile; N/A, not applicable a All C. difficile isolates from 2017 to 2021 submitted to 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 (age 18 years and older) and year-round for children (age 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 (age 18 years and older) and year-round for children (age 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 above CCDR • May 2023 • Vol.49No.5

Table 3 :
Methicillin-resistant Staphylococcus aureus bloodstream infections data, Canada, 2017-2021Between 2017 and 2021, daptomycin non-susceptibility was detected in 18 isolates.All submitted MRSA BSI isolates from 2017 to 2021 were susceptible to linezolid and vancomycin.Comparing HA-MRSA isolates to CA-MRSA isolates, clindamycin resistance was consistently higher among HA-MRSA isolates each year from 2017 (47.3% vs. 36.6%)to2021(36.3% vs. 23.9%)(TableS2.2).There were no other notable differences in antibiotic resistance patterns by MRSA BSI case type.Between 2017 and 2021, the proportion of spa types identified as t002 (CMRSA2) and most commonly associated with MRSA infections acquired in a healthcare setting continued to decrease; from 23.5% of all HA-MRSA isolates in 2017 to 15.6% in 2021.The proportion of spa types identified as t008 (CMRSA10) and most commonly associated with MRSA infections acquired in the community continued to increase and account for the largest proportion of CA-MRSA isolates from 2017 (45.3%) to 2021 (48.9%) (Table Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; 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 2017 to 2021 submitted to National Microbiology Laboratory were susceptible to linezolid 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 .1).Stratified by hospital type, VRE BSI rates remained highest in adult hospitals from 2017 to 2021 (range: 0.29-0.45infections per 10,000 patient days).From 2017 to 2021, VRE BSI rates in paediatric hospitals were low, with zero cases reported in 2021.In 2021, VRE BSI rates were 0.36 infections per 10,000 patient days in both medium (201-499 beds) and large (500+ beds) size hospitals while rates in small (1-200 beds) hospitals have decreased since 2019 (0.35 to 0.14 infections per 10,000 patient days).

Table 4 :
Vancomycin-resistant Enterococcus faecium bloodstream infections data, 2017-2021Vancomycin-resistant Enterococcus BSI were predominantly HA, as 89.9% (n=994/1,106) of VRE BSI reported from 2017 to 2021 were acquired in a healthcare facility.All-cause mortality remained high (32.6%)from2017 to 2021.The incidence rates by region, hospital type and hospital size are presented in TableS3.2.
49breviations: 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 CCDR • May 2023 • Vol.49No.5 DiscussionCNISP surveillance data have shown that between 2017 and 2021 there was a decreasing trend for CDI infection rates (including both HA and CA-cases) in Canada, but rates of MRSA and VRE BSI increased by 35% and 43%, respectively.Rates of CPE infection increased, but remained stable from 2018 to 2021 and few C. auris isolates were identified from 2012 to 2021.

Table 5 :
Carbapenemase-producing Enterobacterales data, Canada, 2017-2021 a All isolates were resistant to ampicillin, and all but one to cefazolin.All carbapenemase-producing organism isolates were screened for the mcr-type gene which is an acquired gene associated with colistin resistance c The denominator for some drugs were adjusted as minimum inhibitory concentration values were not given in all cases due to VITEK ® algorithms d Total number reflects the number of isolates tested for each of the antibiotics listed above e Only found in Serratia marcescens f Some isolates contain multiple carbapenemases therefore the total number of isolates tested and the number of carbapenemases indicated may not match Note: Aggregate mortality data reported in-text due to fluctuations in the small numbers of CPE deaths reported each year Abbreviations: CPE, carbapenemase-producing Enterobacterales; GES, Guiana extended-spectrum β-lactamase; IMP, active-on-imipenem; KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; NMC, not metalloenzyme carbapenemase; N/A, not applicable; OXA-48, Oxacillinase-48; SME, Serratia marcescens enzymes; VIM, Verona integron-encoded metallo-βlactamase a Includes data for all CPE isolates submitted b CCDR • May 2023 • Vol.49 No. 5 To further improve representativeness and generalizability of national HAI benchmark rates, CNISP and Association of Medical Microbiology and Infectious Disease Canada have launched a simplified dataset accessible to all acute care hospitals across Canada to collect and visualize annual HAI rate data.In recent years, CNISP has implemented surveillance for new and emerging pathogens, including C. auris and COVID-19.Studies are ongoing to assess the impact of the COVID-19 pandemic on HAI rates and AMR.