Discussion

We examined the use of antibiotics commonly used for community-onset respiratory infections throughout the first 3 waves of the COVID-19 pandemic in Toronto, Ontario. In the medical wards, a 76% increase in respiratory antibiotic prescribing was observed in wave 1 but not in waves 2 or 3, despite higher numbers of patients admitted to the hospital with COVID-19 in the latter 2 waves. In ICUs, respiratory antibiotic use increased by 30% and 21% in waves 1 and 2, respectively; however, respiratory antibiotic use returned to the baseline in wave 3. Respiratory antibiotic use was similar between institutions (Figs. 1 and 2), and antibiotic use data were compared to a baseline period to adjust for seasonal and institution-specific prescribing trends.

Throughout the COVID-19 pandemic, significant healthcare resource strain has been described, leading to reduced or suspended ASP interventions. ^{Reference Ashiru-Oredope, Kerr and Hughes6–Reference Ng, Tan and Heng8} However, data describing the use of antibiotics in hospitalized patients throughout the many waves of the current pandemic are limited, especially in North America. In our study, clear prescribing trends evolved similarly in 3 large, acute-care hospitals that continued core ASP activities and followed the same regional COVID-19 therapeutic guidelines. Similar to existing publications, we noted an increased use of antibiotics during the pandemic. ^{Reference Stevens, Jensen, Kooda, Mara, O’Horo and Shah16–Reference Henig, Kehat and Meijer19} Compared to existing publications, our antibiotic use metrics were normalized with the use of patient day data, and we adjusted for prior antibiotic prescribing trends and seasonality with the use of an interrupted time-series analysis. We also analyzed antibiotic use between different pandemic waves to examine the evolution of antibiotic prescribing as new publications and guidelines were developed throughout the first 3 waves of the pandemic.

In this study, we observed a large initial increase in respiratory antibiotic prescribing, followed by reduced prescribing in subsequent pandemic waves even though COVID-19 admissions increased with every wave. All authors were involved in the clinical care of COVID-19 patients during the pandemic, and through our experiences, we identified several potential mechanisms and drivers of appropriate antibiotic prescribing. Firstly, the generation of timely scientific research to inform clinical practice and to develop evidence-based guidelines was essential. For example, the systematic living review published in July 2020⁹ was the first large-scale meta-analysis describing the low incidence of bacterial coinfection in patients with COVID-19. Secondly, ASPs benefitted from the rapid development of regional COVID-19 treatment guidelines, which began as an informal initiative among hospitals in the Greater Toronto Area and later was incorporated into an advisory body to the government (Ontario COVID-19 Science Advisory Table). In contrast to some major international guidelines, ^{Reference Bhimraj, Morgan and Shumaker21,22} the Ontario COVID-19 Science Advisory Table guidelines include explicit recommendations against the use of antibiotics unless there is a specific concern for bacterial coinfection. Contributors to these regional consensus guidelines included frontline healthcare clinicians across the province, with diverse backgrounds regarding practice setting (rural and urban centers) and clinical specialty (infectious diseases, antimicrobial stewardship, critical care, ambulatory care, and patient partners). Finally, involvement of ASPs in regional guideline development and as local content experts facilitated knowledge translation and implementation of evidence-based guidelines. This process occurred both at the individual patient level via prospective audit and feedback and at the system level via interventions such as order sets and institution-wide continuing education initiatives. Each of these potential mechanisms are closely linked and act in tandem; new research is needed to inform the development of evidence-based guidelines, which then empowers individual ASP initiatives to optimize antibiotic use.

Although our results do not prove causation, our findings may indicate that local and regional ASP initiatives and resources were successful in reducing unnecessary antibiotic use in patients with COVID-19. Despite the pandemic-associated challenges for each institution’s ASP, all programs maintained some form of prospective audit and feedback (the gold standard, and guideline-recommended approach/cornerstone for ASPs) ^{Reference Barlam, Cosgrove and Abbo23} throughout the pandemic, and we observed that prescribing trends changed similarly across all study sites despite the local variations in ASP activities. Thus, we hypothesize that the combinations of a variety of ASP approaches were successful at changing prescribing behavior and that regional guidelines also contributed to improving antibiotic prescribing practices throughout the pandemic. Notably, a Public Health Ontario survey of all hospitals in the province reported that the pandemic may have had less adverse impact on core ASP activities and ASP funding in Ontario, compared to programs in other jurisdictions. ^{Reference So and Leung24}

Although our study observed similar trends of local respiratory antibiotic prescribing during the pandemic, it had several limitations. Although our results are hypothesis generating, our descriptive study could not identify the causative factors specifically responsible for the initial increase, and subsequent normalization of respiratory antibiotic prescribing during the first 3 waves of the COVID-19 pandemic across our institutions. We only included antibiotics recommended for community-acquired lower respiratory infection to best capture the direct impact of COVID-19 on antimicrobial prescribing. We did not have access to indications for antimicrobial therapy, thus our utilization data may have included antibiotics used for indications other than respiratory tract infection and may have excluded some patients who received broader antimicrobial coverage for bacterial coinfection. We were also unable to identify and exclude a small amount of study-related antibiotic prescribing (eg, REMAP-CAP ^{Reference Angus, Berry and Lewis25} ). In addition, we were not able to restrict our study population solely to patients with COVID-19, due to limitations of administrative data. Thus, we selected a nonconventional metric of COVID-19 admissions per 1,000 PD. Our selected study units were chosen because they represent the admitting units for most COVID-19 patients at our institutions. Another factor that may have influenced our study results is the possible change in patient demographics across our study units throughout the pandemic (eg, surgical units may have taken patients who would usually be admitted to a medicine ward for bed-spacing purposes). Patient demographics may also have varied between our institutions, which could have contributed to variances from observed baseline antibiotic prescribing patterns. We attempted to control for these variances by including a local baseline use period and adjustment for seasonality, which provided a local historical comparator. Our chosen metric (DOT/1,000 PD) did not specifically assess appropriateness of antibiotic prescribing; however, the continuation of our local prospective audit-and-feedback programs regularly assessed antibiotic appropriateness in real time throughout the pandemic. Furthermore, as all 3 sites had comprehensive ASPs consisting of a variety of interventions (both prior to and during the pandemic), we were not able to directly identify which specific ASP intervention(s) may have driven our observations or whether additive or synergistic effects exist with multiple ASP interventions. Finally, it is unclear whether our observations are representative of other regional or international institutions, which may have had differing prepandemic ASP resources and may have faced different pandemic-related limitations or local pressures.

In summary, after an initial surge in respiratory antibiotic prescribing, we observed the normalization of prescribing trends at 3 large hospitals throughout the first 3 waves of the COVID-19 pandemic in Toronto, Ontario. Although exact causation could not be established, our results suggest that our ASPs were successful at decreasing respiratory antibiotic use by maintaining core antimicrobial stewardship activities, despite significant resource strains throughout the pandemic. Timely generation of new research and evidence, and rapid knowledge translation into guidelines with the involvement of frontline clinicians and local stakeholders, may have contributed to the success of our ASPs. Our study illustrates the essential nature of ASPs for both monitoring and influencing antibiotic prescribing trends; therefore, it is important to support the growth and development of ASPs, especially in situations in which the overuse of antibiotics is likely to occur.