key: cord-0786668-mx6lii5b
authors: Winders, Hana R.; Bailey, Pamela; Kohn, Joseph; Faulkner-Fennell, Carmen M.; Utley, Sara; Lantz, Evan; Sarbacker, Lloyd; Justo, Julie Ann; Bookstaver, P. Brandon; Weissman, Sharon; Ruegner, Hannah; Al-Hasan, Majdi N.
title: Change in Antimicrobial Use during COVID-19 Pandemic in South Carolina Hospitals: A Multicenter Observational Cohort Study
date: 2021-10-13
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106453
sha: 9258bb0ff94a67698b35d9078266158928e48d2d
doc_id: 786668
cord_uid: mx6lii5b

This retrospective cohort study examined the impact of the pandemic on antimicrobial use (AU) in South Carolina hospitals. AU in days of therapy (DOT) per 1000 days-present was evaluated in 17 hospitals in South Carolina. Matched-pairs mean difference was used to compare AU during the pandemic (March-June 2020) to that during the same months in 2019 in hospitals that did and did not admit patients with COVID-19. There was a 6.6% increase in overall AU in the 7 hospitals admitting patients with COVID-19 (from 530.9 to 565.8; mean difference: 34.9 DOT/1000 days-present, 95% CI: 4.3, 65.6; p=0.03). There was no significant change in overall AU in the remaining 10 hospitals that did not admit patients with COVID-19 (mean difference 6.0 DOT/1000 days-present, 95% CI: -55.5, 67.6; p=0.83). Most of the increase in AU in the 7 hospitals that admitted patients with COVID-19 was observed in broad-spectrum antimicrobial agents. A 16.4% increase was observed in agents predominantly used for hospital-onset infections (from 122.3 to 142.5; mean difference: 20.1 DOT/1000 days-present, 95% CI: 11.1, 29.1, p=0.002). There was also a 9.9% increase in the use of anti-MRSA agents (from 66.7 to 73.3; mean difference: 6.6 DOT/1000 days-present, 95% CI: 2.3, 10.8; p=0.01). COVID-19 pandemic appears to drive overall and broad-spectrum antimicrobial use in South Carolina hospitals admitting patients with COVID-19. Additional antimicrobial stewardship resources are needed to curtail excessive antimicrobial use in hospitals to prevent subsequent increases in antimicrobial resistance and Clostridioides difficile infection rates given the continuing nature of the pandemic.

This retrospective cohort study examined the impact of the pandemic on antimicrobial use (AU) in South Carolina hospitals. AU in days of therapy (DOT) per 1000 days-present was evaluated in 17 hospitals in South Carolina. Matched-pairs mean difference was used to compare AU during the pandemic (March-June 2020) to that during the same months in 2019 in hospitals that did and did not admit patients with COVID-19. There was a 6.6% increase in overall AU in the 7 hospitals admitting patients with COVID-19 (from 530.9 to 565.8; mean difference: 34.9

DOT/1000 days-present, 95% CI: 4.3, 65.6; p=0.03). There was no significant change in overall AU in the remaining 10 hospitals that did not admit patients with COVID-19 (mean difference 6 .0 DOT/1000 days-present, 95% CI: -55.5, 67.6; p=0.83). Most of the increase in AU in the 7 hospitals that admitted patients with COVID-19 was observed in broad-spectrum antimicrobial agents. A 16.4% increase was observed in agents predominantly used for hospital-onset 

Due to the novel nature of the COVID-19 pandemic, little was known initially regarding bacterial coinfection rates with this viral pneumonia. Early in the pandemic, up to three-quarters of hospitalized adults with COVID-19 were prescribed empiric antibacterial agents [1] [2] [3] . As the pandemic progressed, evidence emerged that bacterial co-infections ranged from 3.5-8.1% in hospitalized patients with COVID-19 [3] [4] [5] [6] . Within the United States, there were notable increases in antimicrobial prescribing rates, including broad spectrum antimicrobials, with more severe COVID-19 disease presentation [3] .

Antimicrobial stewardship programs (ASPs) are critical components of hospital safety and quality teams, as they play an essential role in developing local treatment guidelines and assisting frontline healthcare providers [7] . ASPs have longstanding roles in optimizing selection of empiric antimicrobial therapy and assisting with targeted de-escalation [8] . However, during the initial days of the pandemic, many ASP resources were repurposed to support healthcare system's needs during the pandemic, limiting their time for dedicated ASP initiatives [9] . This reprioritization of ASP workflow, the lack of clinical data, and modifications in ASP team dynamics with front-line providers during the pandemic created the potential for amplification of inappropriate antimicrobial prescribing [9] .

The aim of this multicenter retrospective observational cohort study was to compare overall and broad-spectrum antimicrobial use during the pandemic (March-June 2020) to the same months of the previous year in hospitals that admitted patients with COVID-19 and those that did not admit patients with COVID-19 in South Carolina. 6 

Overall antimicrobial use for all antibacterial agents, broad spectrum antibacterial agents predominantly used for hospital-onset infections, broad spectrum antibacterial agents predominantly used for community-acquired infections, and antibacterial agents predominantly used for resistant Gram-positive infections were collected from NHSN's antimicrobial use option.

Broad spectrum antibacterial agents predominantly used for hospital-onset infections included antipseudomonal penicillins, cephalosporins, carbapenems, and aminoglycosides. Broad spectrum agents predominantly used for community-acquired infections included third generation cephalosporins and fluoroquinolones. Antibacterial agents predominantly used for resistant Gram-positive infections included vancomycin and other agents with activity against 7 methicillin-resistant Staphylococcus aureus (MRSA) [10] . From NHSN, standardized antimicrobial administration ratios (SAARs), a ratio of reported antimicrobial days over statistically modeled antimicrobial days, was also included to more easily compare AU between hospitals [11] . 

Seventeen of 22 invited hospitals (77%) agreed to participate in the study. Of the 17 included hospitals in the analysis, 7 admitted patients with COVID-19 in March-June 2020 and the remaining 10 did not. Hospitals admitting patients with COVID-19 were relatively larger, more likely to have in-house ASPs (a pharmacist or physician available within that hospital), and had a lower baseline standardized antimicrobial administration ratios (SAARs) in 2019 than comparators (Table 1) .

In the 7 hospitals admitting patients with COVID-19, there was a significant increase in overall antimicrobial use during the pandemic (mean difference 34.9 DOT/1000 days-present; 95% CI: 4.3, 65.6; p=0.03; Figure 1 ). This corresponded to a 6.6% increase in overall antimicrobial use from March-June 2019 to the same months in 2020. Most of the increase in antimicrobial use in these 7 hospitals was observed in broad-spectrum agents predominantly used for hospital-onset infections (16.4% increase from 122.3 in 2019 to 142.5 DOT/1000 days-present in 2020). There was also a 9.9% increase in the use of broad-spectrum gram-positive agents in these 7 hospitals from 66.7 to 73.3 DOT/1000 days-present. 9 

There were no significant changes in overall antimicrobial use, broad-spectrum agents predominantly used for hospital-onset infections, or broad-spectrum gram-positive agents in hospitals that did not admit patients with COVID-19. To the contrary, there was a significant decline in antimicrobial use of broad-spectrum agents predominantly used for communityacquired infections in these hospitals in March-June 2020 compared to 2019 (Table 1; Figure 1 ).

There was a significant increase in the overall antimicrobial use in the South Carolina hospitals that admitted patients with COVID-19 during the pandemic when compared to the same time period in the previous year. Increases were specifically observed in the use of broad-spectrum agents, particularly anti-pseudomonal beta-lactams and anti-MRSA agents. Interestingly, similar increases in antimicrobial use were not demonstrated in hospitals that did not admit patients with COVID-19. Treating patients with COVID-19 appears to drive overall and broad-spectrum antimicrobial use in hospitals.

The COVID-19 pandemic imposes unprecedented challenges on ASPs and threatens to erase the gains made in this field over the past several years. A multicenter cohort study of 84 Veterans Administration hospitals in the United States recently reported a decline in antimicrobial use from 2015 through 2019 [12] . However, the increase in antimicrobial use observed in January-May 2020 negated the prior years of antimicrobial stewardship improvements [12] . Reports of increased antimicrobial use early in the COVID-19 pandemic also emerged from single medical centers in the United States and Singapore [13] [14] [15] . To our knowledge, this is the first study to contrast the change in antimicrobial use during the pandemic in hospitals that did and did not admit patients with COVID-19.

The increase in overall antimicrobial use during the pandemic is concerning. However, the steeper rise in the use of broad-spectrum agents in hospitals admitting patients with COVID-19 is 11 even more alarming. These results are consistent with a recent large review reporting >70% of patients with COVID-19 receiving antimicrobials, a majority being broad-spectrum antibacterial agents [2, 4] . This is despite low incidence of bacterial co-infection ranging from 5.9% in all hospitalized patients to 8.1% in critically ill patients, with bacterial superinfections reported as high as 20% [4, 16] . The most common organisms identified in superinfections include Acinetobacter spp., Pseudomonas, and Escherichia coli, indicating likely need for broadspectrum coverage, but the risks of these agents must be considered [16] . The increasing use of broad spectrum agents predominantly used for hospital-onset infections in the current study is particularly concerning for antimicrobial stewards given the high risk of hospital-onset Clostridioides difficile infections associated with the heavy use of these broad-spectrum agents [8, 17] . Although some aspects of infection prevention, such as hand hygiene, personal protective equipment, and environmental hygiene, are heightened, other risks for nosocomial spread of infection have lessened monitoring, such as contact isolation, admission screening, and ASP [9] .

In New York City, worsening Enterobacterales susceptibility rates during the pandemic was observed compared to 2018-2019 data [5] . The spread of carbapenem-resistant Gram-negative bacteria and Candida auris was described in acute care hospitals and intensive care units during the peak of the pandemic in Italy and the United States [18] [19] [20] . Specific lapses in standard infection prevention practices were noted [20] .

In addition to increased antimicrobial use in hospitalized patients with COVID-19, other structural changes to ASP during the pandemic likely influenced the study results. Stevens and colleagues discussed the many roles ASP members may play in COVID-19 response efforts 12 including assisting with creating treatment guidelines and facilitating use of medications approved by emergency use authorization [7] . In South Carolina, many ASP members had their workloads redirected towards other duties like procuring and facilitating remdesivir usage as well as developing guidelines for its usage and covering non-ASP related tasks for pharmacy furloughs. Diversion of ASP resources may also limit the effectiveness of antimicrobials postprescription audit and feedback interventions. Although all hospitals admitting patients with COVID-19 in South Carolina had in-house ASP and robust baseline antimicrobial use metrics based on 2019 SAAR data, they were not immune from the great challenges posed by the COVID-19 pandemic. All these factors likely contributed to higher overall and broad-spectrum antimicrobial use during the pandemic in hospitals admitting patients with COVID-19. It is speculated that less disruption in ASP's daily workflow likely resulted in stable overall antimicrobial use during the pandemic in hospitals that did not admit patients with COVID-19 and even a decline in one category possibly due to ongoing efforts to reduce already high baseline antimicrobial use.

The multicenter design and accounting for seasonal variation in antimicrobial use by comparing March-June 2020 to the same months in 2019 represent the major strengths in this investigation.

The study shares common limitations of observational cohorts, including not accounting for unknown or unmeasured confounders. In addition, the study examines quantitative antimicrobial use in hospitals and does not include patient-level data to assess appropriateness, including potential increases in intensive care population during the COVID-19 pandemic or decreases in AU due to cancelled elective procedures. There is speculation about sicker population making up 13 hospital admissions other than COVID-19 patients during the pandemic, affecting antimicrobial use, but this has not yet been quantified. In one study of hospitals admissions during the pandemic, largely flat mortality rates imply total in-hospital deaths decreased on par with decreased in hospital admissions, so the assumption of sicker patients still seeking medical care may not bear out [21] . It remains undetermined whether the increase in antimicrobial use in COVID-19 admitting hospitals was mostly due to excessive antimicrobial use in patients with COVID-19 or disruption of routine antimicrobial stewardship activities. The proportion of hospital admissions due to COVID-19 that early in the pandemic was not available in most COVID-19 admitting hospitals. There was a numerical overall decline in hospital occupancy in all participating hospitals in the study likely due to suspension of elective procedures and other mitigation policies early in the pandemic in South Carolina. The specific impact of these changes on patient demographics were not measured in this study. Finally, the current study was confined to a specific geographical area so the results may not be generalizable to other regions.

A significant increase in overall and broad-spectrum antimicrobial use was observed in hospitals admitting patients with COVID-19 in South Carolina. The pandemic continues to stress and test the resilience of healthcare systems and ASPs alike. At a time when resources may be limited, keeping the focus on patient safety and quality teams within hospitals is more important than ever before. Healthcare providers must continue to work together towards judicious antimicrobial use in the face of our developing knowledge regarding COVID-19. Antimicrobial use is reported in days of therapy per 1000 days-present. Error bars indicated 95% confidence intervals.

Coronavirus disease 2019, superinfections, and antimicrobial development: What can we expect?

Antibiotic prescribing in patients with COVID-19: rapid review and meta-analysis

Empiric antibacterial therapy and community-onset bacterial co-infection in patients hospitalized with COVID-19: a multi-hospital cohort study

Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis

Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge

Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing

Involving antimicrobial stewardship programs in COVID-19 response efforts: All hands on deck

Role of early de-escalation of antimicrobial therapy on risk of Clostridioides difficile infection following Enterobacteriaceae bloodstream infections

COVID-19 and the potential long-term impact on antimicrobial resistance

The standardized antimicrobial administration ratio: a new metric for measuring and comparing antibiotic use

Direct measurement of performance: a new era in antimicrobial stewardship

Inpatient antibiotic utilization in the Veterans Administration during the coronavirus disease 2019 (COVID-19) pandemic

Impact of COVID-19 on pneumonia-focused antibiotic use at an academic medical center

Antimicrobial stewardship programme: a vital resource for hospitals during the global outbreak of coronavirus disease 2019 (COVID-19)

Antibiotic prescription during the COVID-19 pandemic: A biphasic pattern

Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. PloS one

Electronically available comorbid conditions for risk prediction of healthcare-associated Clostridium difficile Infection

Spread of carbapenem-resistant Gram-negatives and Candida auris during the COVID-19 pandemic in critically ill patients: One step back in antimicrobial stewardship?

Increase in hospitalacquired carbapenem-resistant Acinetobacter baumannii infection and colonization in an acute care hospital during a surge in COVID-19 admissions -New Jersey

The impact of the COVID-19 pandemic on hospital admission in the United States

The authors thank all team members of the antimicrobial stewardship programs in the 17 participating hospitals in the study and the Antimicrobial Stewardship Collaborative of South Carolina.HRW and MNA have full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the analysis.