Healthcare-associated infections and antimicrobial resistance in Canadian acute care hospitals, 2014-2018.

Background
Healthcare-associated infections (HAIs) and antimicrobial resistance (AMR) pose serious threats to the health of Canadians due to increased morbidity, mortality and healthcare costs. Epidemiologic and laboratory surveillance data, collected through the Canadian Nosocomial Infection Surveillance Program, are used to inform infection prevention and control and antimicrobial stewardship programs and policies. The objective of this study was to describe the epidemiologic and laboratory characteristics and trends of HAIs and AMR from 2014 to 2018 using surveillance data provided by Canadian hospitals participating in the Canadian Nosocomial Infection Surveillance Program.


Methods
Data were collected from 70 Canadian sentinel hospitals between January 1, 2014 and December 31, 2018 for Clostridioides difficile infection (CDI), methicillin-resistant Staphylococcus aureus bloodstream infections, vancomycin-resistant Enterococci bloodstream infections and carbapenemase-producing Enterobacteriaceae. Case counts, rates, outcome data, molecular characterization and antimicrobial resistance profiles are presented. Additionally, hospital-level Escherichia coli antibiogram data were collected and are described.


Results
Increases in rates per 10,000 patient-days were observed for methicillin-resistant S. aureus bloodstream infections (59%; 0.66-1.05, p=0.023) and vancomycin-resistant Enterococci bloodstream infections (143%; 0.14-0.34, p=0.023). However, CDI rates decreased by 12.5% between 2015 and 2018 (from 6.16-5.39, p=0.042). Carbapenemase-producing Enterobacteriaceae infection rates remained low and stable whereas colonization increased by 375% (0.04-0.19; p=0.014).


Conclusion
Ongoing efforts to prevent HAIs and reduce AMR in Canada require consistent, standardized surveillance data from acute care hospitals. Increased collaboration with provincial, territorial and international partners in infection prevention and control, as well as antimicrobial stewardship, will be essential in reducing the burden of observed HAIs (including antimicrobial resistant organisms).


Introduction
Healthcare-associated infections (HAIs) including antimicrobial resistant organisms (AROs) pose a serious risk to the safety and quality of care delivered to patients globally, including in Canada. HAIs cause significant morbidity and mortality among patients and result in increased healthcare costs (1)(2)(3)(4). A 2017 point prevalence survey among participating Canadian hospitals estimated that 7.9% of patients had at least one HAI; results that are similar to those from a 2016-2017 study by the European SURVEILLANCE Centre for Disease Prevention and Control that estimated HAI prevalence among tertiary care hospitals to be 7.1% (5,6). A study conducted in the European Union and European Economic Area in 2015 estimated that 2,609,911 new cases of HAI occur every year, corresponding to an annual burden of 501 disability-adjusted life years per 100,000 general population (7).
Antimicrobial resistance (AMR) is a growing healthcare concern, with increased resistance levels detected in humans worldwide (8). Antimicrobial resistant infections cause at least 50,000 deaths each year across Europe and the United States (US) alone (9). Close monitoring of AMR is vital for detecting and responding to emerging trends and patterns of resistance and thus to effectively controlling and treating HAIs.
In Canada, the Public Health Agency of Canada (PHAC) collects national data on various HAIs and AMR through the Canadian Nosocomial Infection Surveillance Program (CNISP). This program was established in 1995 as a partnership between PHAC, the Association of Medical Microbiology and Infectious Disease Canada and sentinel hospitals across Canada. The goal of CNISP is to help facilitate the prevention, control and reduction of HAIs and AROs in Canadian acute care hospitals through active surveillance and reporting.
Reflecting the core components of infection prevention and control of the World Health Organizations (10), CNISP performs consistent, uniform surveillance to reliably measure HAI burden, establish benchmark rates for internal and external comparison, identify potential risk factors and allow for the assessment of specific interventions to improve the quality of patient care. Data provided by CNISP directly supports the goals outlined in the 2017 Pan-Canadian Framework for Action for tackling antimicrobial resistance and antimicrobial use (11).
In this report, we describe the most recent HAI and AMR surveillance data collected from CNISP participating hospitals between 2014 and 2018.

Methods Design
Canadian Nosocomial Infection Surveillance Program conducts prospective, sentinel surveillance for HAIs (including AROs) and collects annual hospital-level antibiograms.

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
Epidemiologic data: Between January 1, 2014 and December 31, 2018, participating hospitals submitted epidemiologic data on cases meeting the respective case definitions for Clostridioides difficile infection (CDI), methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA BSI), vancomycin-resistant Enterococci bloodstream infections (VRE BSI) and carbapenemase-producing Enterobacteriaceae (CPE) infections and colonizations. Community-associated CDI surveillance was launched in 2015 and CA-CDI cases have been included since then. In 2018, 70 hospitals across Canada participated in HAI surveillance and are further described in Table 1.
Participating hospitals submitted epidemiologic (demographic, clinical and outcome data) and denominator data (associated patient-days and patient-admissions) electronically through the Canadian Network for Public Health Intelligence platform; a secure on-line data entry system. Standardized protocols and case definitions were reviewed annually by expert working groups and annual training sessions were provided for data submission. Data quality within CNISP projects has been evaluated periodically (12,13).
Laboratory data: Patient-linked laboratory isolates were sent to the PHAC's National Microbiology Laboratory (NML) for molecular characterization and susceptibility testing. MRSA BSI, VRE BSI, CPE and pediatric CDI isolates were submitted year round. Adult CDI isolates were submitted during a targeted two-month period from March 1 to April 30 each year.

Vancomycin-resistant Enterococci bloodstream infections
From 2014 to 2018, VRE BSI rates have increased by 143% from 0.14 to 0.34 infections per 10,000 patient-days (p=0.023) ( Table 4). The VRE BSI rates were highest in Central and Western Canada (0.42 and 0.33 infections per 10,000 patient-days respectively) with few VRE BSIs reported in Eastern Canada (0.01 infections per 10,000 patient-days) (

Carbapenemase-producing Enterobacteriaceae
From 2014 to 2018, the CPE infection rates remained low and stable (0.04 infections per 10,000 patient-days), while a nearly five-fold increase in colonization rates was observed (p=0.014) (     (19,20). Decreased Canadian CDI rates suggest improvements in infection prevention and control practices in hospitals, such as hand hygiene compliance, environmental cleaning, antibiotic stewardship and increased awareness of infection (21).
An increase in the rates of MRSA BSI, attributed to the increase in CA-MRSA BSI rates, is raising concerns as these infections are associated with a mortality rate higher than 20% among admitted patients (22). As MRSA resistance trends are closely tied to the prevalence of epidemic strains, the decrease in the proportion of strain types that are identified as CMRSA2 is driving down clindamycin resistance among isolates (23). The incidence of MRSA BSI in 2017 was lower than the rates reported by South Korea (0.84 versus 1.6 infections per 10,000 patient days) (24). In a US study, reported medium-sized US hospital-onset MRSA BSI rates between 2016 and 2017 were slightly lower than were healthcare-associated 2017 MRSA BSI rates in Canada (0.45 versus 0.47 infections per 10,000 patientdays), but rates for large US hospitals were higher (0.54 versus 0.42 infections per 10,000 patient-days) (25).
The increase in VRE BSI rates in Canada is a concerning trend as hospitalized patients with VRE bacteremia have a higher risk of mortality and longer length of stay when compared with vancomycin-susceptible Enterococcus bacteremia (26). This increase may be due to differences in infection control practices across acute care hospitals, with some hospitals discontinuing the practice of admission screening and use of contact precautions for infected and colonized patients (27).
Laboratory surveillance of VRE isolates revealed an emerging strain, ST1478, associated with daptomycin non-susceptibility and high-level gentamicin resistance. First identified in Australia (28,29), pstS negative sequence types emerged in Canada primarily through the identification of ST1478 and may be associated with increased rates of VRE BSI (30). Further investigation is ongoing to understand the emergence and transmission dynamics of this novel strain in Canada.

Defined as antibiotics of last resort by the World Health
Organization, carbapenems are now threatened by the emergence of carbapenem-resistant organisms (31). While observed CPE rates are low in Canada, colonizations increased nearly five-fold from 2014 to 2018. Changes in screening practices may have contributed to the increase in reported colonization rates and will be collected moving forward (13). National surveillance suggests increases in CPE are driven by local nosocomial transmission as well as travel and healthcare from endemic areas, as has been reported in Ontario (32). There is continued need for the coordination of infection control measures and surveillance to prevent further transmission of CPE in Canadian acute care hospitals.
Antibiogram data has confirmed that antibiotic susceptibility to E. coli has changed minimally in Canada from 2014-2018. Standardized, routine reporting on AMR data through CNISP contributes to crucial international collaborative initiatives such as the World Health Organization Global Antimicrobial Resistant Surveillance System (33).
Consistent and uniform surveillance that helps to inform infection control practices and antimicrobial stewardship programs are essential to reducing the rates of infection and AMR, both of which cause substantial increases in healthcare costs, morbidity and mortality (15).

Strengths and limitations
The main strength of CNISP surveillance data is the active collection of standardized, detailed, epidemiologic and laboratory-linked data from 70 sentinel hospitals across Canada. However, it is primarily large, tertiary acute care hospitals that participate in CNISP, and these hospitals may not fully represent the general Canadian inpatient population. The CNISP is currently undergoing a recruitment process in order to increase representativeness and coverage of Canadian inpatient beds, especially in Northern, rural community and indigenous populations.
The CNISP data, although standardized, may be sensitive to changes in hospital participation infection prevention and control practices and the application of surveillance definitions.

Next steps
Continued recruitment of hospitals into the CNISP network with a 2020 goal of 33% national acute-care bed coverage from all ten provinces and three territories will improve the quality and representativeness of HAI estimates in Canada. To address gaps in surveillance data, detailed hospital screening practice surveys will be conducted annually to better interpret changes in HAI rates. Additionally, steps have been taken to gauge interest in the surveillance of non-acute care settings within the CNISP network such as long-term care facilities. Epidemiologic and laboratory-led working groups were also formed to investigate new and emerging pathogens such as Candida auris and VRE BSI ST1478. Lastly, future CNISP antibiogram data aims to report on a broader range of patient and specimen types as well as reporting resistance data on K. pneumoniae, pseudomonas, acinetobacter and S. aureus.

Conclusion
Ongoing efforts to prevent HAIs, including AROs, and to reduce AMR in Canadian acute-care hospitals require standardized surveillance and consistent infection prevention and control practices. Data presented in this article indicate rates of MRSA BSI, VRE BSI and CPE colonizations increased substantially between 2014 and 2018 while rates of CDI decreased. These findings indicate a need for continued vigilance to prevent morbidity and mortality attributable to HAIs and AROs in the inpatient population. As new pathogens emerge, and resistance to last-resort antibiotics is identified, PHAC's continued partnership with acute-care hospitals and collaboration with provincial, territorial and international partners in infection prevention and control as well as antimicrobial stewardship are essential to reducing the burden of HAIs and AROs in Canada.

Authors' statement
Canadian Nosocomial Infection Surveillance Program hospitals provided expertise in the development of protocols in addition to epidemiological data and lab isolates. National Microbiology Laboratory completed the laboratory analyses and contributed to the interpretation and revision of the paper. Epidemiologists from Public Health Agency of Canada were responsible for the conception, analysis, interpretation, drafting, and revision of the paper.

Funding
This work was supported by Public Health Agency of Canada.

Clostridioides difficile infection (CDI)
A "primary" episode of CDI is defined as either the first episode of CDI ever experienced by the patient or a new episode of CDI, which occurs greater than eight weeks after the diagnosis of a previous episode in the same patient.
A patient is identified as having CDI if: • The patient has diarrhea or fever, abdominal pain and/or ileus AND a laboratory confirmation of a positive toxin assay or positive polymerase chain reaction (PCR) for C .difficile (without reasonable evidence of another cause of diarrhea) OR • The patient has a diagnosis of pseudomembranes on sigmoidoscopy or colonoscopy (or after colectomy) or histological/pathological diagnosis of CDI OR • The patient is diagnosed with toxic megacolon (in adult patients only) Diarrhea is defined as one of the following: • More watery/unformed stools in a 36-hour period • or more watery/ unformed stools in a 24-hour period and this is new or unusual for the patient (in adult patients only) Exclusion: • Any patients younger than one year • Any pediatric patients (aged one year to younger than 18 years) with alternate cause of diarrhea found (i.e. rotavirus, norovirus, enema or medication, etc.) are excluded even if C. difficile diagnostic test result is positive CDI case classification Once a patient has been identified with CDI, the infection will be classified further based on the following criteria and the best clinical judgment of the healthcare and/or infection prevention and control practitioner.

Healthcare-associated (acquired in your facility) CDI case definition
• Related to the current hospitalization o The patient's CDI symptoms occur in your healthcare facility three or more days (or ≥72 hours) after admission • Related to a previous hospitalization o Inpatient: The patient's CDI symptoms occur less than three days after the current admission (or less than 72 hours) AND the patient had been previously hospitalized at your healthcare facility and discharged within the previous four weeks o Outpatient: The patient presents with CDI symptoms at your emergency room (ER) or outpatient location AND the patient had been previously hospitalized at your healthcare facility and discharged within the previous four weeks • Related to a previous healthcare exposure at your facility o Inpatient: The patient's CDI symptoms occur less than three days after the current admission (or less than 72 hours) AND the patient had a previous healthcare exposure at your facility within the previous four weeks o Outpatient: The patient presents with CDI symptoms at your ER or outpatient location AND the patient had a previous healthcare exposure at your facility within the previous four 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 less than 12 weeks after the patient was discharged from any healthcare facility or after the patient had any other healthcare exposure. The MRSA infection would be considered HA if all elements of a CDC/NHSN site-specific infection criterion were present on or after the third calendar day of admission to the facility (the day of hospital admission is calendar day 1). The MRSA infection would be considered CA if all elements of a CDC/NHSN site-specific infection criterion were present during the two calendar days before the day of admission, the first day of admission (day 1) and/or the day after admission (day 2) and are documented in the medical record.

MRSA bloodstream infection (bacteremia)
To be considered a MRSA bloodstream infection the patient must have MRSA cultured (lab-confirmed) from at least one blood culture. Healthcare-associated is defined as an inpatient who meets the following criteria and in accordance with the best clinical judgement of the healthcare and/or infection prevention and control practitioner: • Exposure to any healthcare setting (including long-term care facilities or clinics) in the previous 12 months OR • Patient is on calendar day 3 of their hospitalization

Carbapenemase-producing Enterobacteriaceae (CPE)
Any patient admitted to a participating CNISP hospital with a hospital laboratory confirmation (and subsequent confirmation by the National Microbiology Laboratory) that tested/screened positive for a least one potential carbapenem-reduced susceptible Enterobacteriaceae, from any body site that meets the Clinical & Laboratory Standards Institute criteria.
Carbapenems are a class of beta-lactam antibiotics with broad-spectrum activity recommended as first-line therapy for severe infections caused by certain gram negative organisms and as directed therapy for organisms that are resistant to narrower spectrum antibiotics.
Carbapenem resistance can be due to changes in the permeability of the organism to the antibiotic and/or the upregulation of efflux systems that "pump" the antibiotic out of the cell, usually concomitant with the presence of an acquired extended-spectrum beta-lactamase or AmpC enzyme or the hyperproduction of intrinsic chromosomally-located betalactamase(s). More recently, resistance is increasingly due to the acquisition of enzymes that break down the carbapenems: carbapenemases (e.g. New Delhi metallo-ß-lactamase-1, Oxacillinase-48, Klebsiella pneumoniae carbapenemase, Verona integrin-encoded metallo-ß-lactamase, active-on-imipenem, etc.). These latter subsets of carbapenem-resistant organisms are called carbapenemase-producing organisms (CPOs) and are of particular concern because of their ability to transfer resistance easily across different genera and species of bacteria. They are quickly becoming a public health problem not only because of the ability to cause healthcare acquired infections which have limited treatment options, but because of the potential for colonizing both inpatient and outpatient populations due to their ease of transmissibility, thus, creating a reservoir of bacterial resistance.
The data presented in this report include Enterobacteriaceae spp. that are resistant to carbapenems through the production of a carbapenemase. The first positive isolate from an inpatient identified as colonized or infected with CPE is eligible. Subsequent positive isolates from the same patient in the same calendar year are eligible only if the patient tests positive for a different carbapenemase. If the patient was initially colonized and subsequently develops an infection with the same gene, within the same calendar year, only the infection is eligible for inclusion in surveillance. Data from previous years included in this report have been adjusted to reflect this change in reporting.