Discussion

In this retrospective multicenter ecological study, the AU rate for broad-spectrum antibacterial agents predominantly used for hospital-onset infections was greater in COVID-19 patients compared to non–COVID-19 patients in COVID-19 and pre–COVID-19 periods in all 3 hospitals facility-wide, and in major ICUs of 2 of 3 hospitals. In contrast, AU rates were lower for all antibacterial agents in non–COVID-19 patients during the COVID-19 period compared to the pre–COVID-19 period. Increased AU rates for broad-spectrum antimicrobials in COVID-19 patients likely resulted from diagnostic and therapeutic uncertainty in the context of high mortality rates in the beginning of the pandemic, ^{Reference Bhatraju, Ghassemieh and Nichols1,Reference Richardson, Hirsch and Narasimhan2} whereas reduced AU rates for all antibacterial agents in non–COVID-19 patients during the pandemic may have reflected changes in inpatient populations.

Rates of facility-wide use of broad-spectrum antibacterial agents predominantly used for hospital-onset infections (eg, cefepime, meropenem, piperacillin-tazobactam), azithromycin, ceftriaxone, and vancomycin were significantly greater in COVID-19 patients compared to non–COVID-19 patients in at least 2 of 3 hospitals. Empiric administration of broad-spectrum antimicrobials by healthcare providers likely resulted from difficulties in differentiating between bacterial and nonbacterial causes of systemic inflammatory response syndrome such as virus-induced inflammation and cytokine storm. ^{Reference Vaughn, Gandhi and Petty11–Reference Garcia-Vidal, Sanjuan and Moreno-Garcia14} Moreover, exacerbations in underlying comorbidities triggered by COVID-19 (eg, congestive heart failure) ^{Reference Creel-Bulos, Hockstein, Amin, Melhem, Truong and Sharifpour21} and complications of COVID-19 (eg, thrombosis and pulmonary embolism) ^{Reference Bilaloglu, Aphinyanaphongs, Jones, Iturrate, Hochman and Berger22,Reference Godoy, Goligher, Lawler, Slutsky and Zarychanski23} can result in critical illness and can trigger the administration of broad-spectrum antimicrobials. Empiric administration of vancomycin was likely driven by the same factors because prescribers often overestimate the occurrence of methicillin-resistant Staphylococcus aureus as a causative agent for infection in inpatient settings. ^{Reference Santos, Martinez and Won24}

The administration of ceftriaxone and azithromycin to COVID-19 patients was likely driven by empiric coverage for community-acquired pneumonia. ^{Reference Vaughn, Gandhi and Petty11} Ceftriaxone and azithromycin administration was especially high in March 2020 in the setting of constrained testing capacity for SARS-CoV-2 at the onset of the pandemic, ^{Reference Hanson, Caliendo and Arias25} likely leading healthcare providers to cover for bacterial infection given diagnostic uncertainty. In addition, the very high use of azithromycin for COVID-19 patients in March 2020 was likely due to its promotion as a repurposed drug for COVID-19 in response to its purported anti-inflammatory and antiviral properties that were later disproven in randomized controlled trials. ^{Reference Oldenburg, Pinsky and Brogdon4,Reference Hinks, Cureton and Knight5} The marked decrease in azithromycin use starting in April 2020 was likely due to its QTc-prolonging effects, especially when coadministered with hydroxychloroquine, another medication alleged to have antiviral properties against COVID-19 on the basis of in vitro information that was also disproven in randomized controlled trials. ^{Reference Avezum, Oliveira and Oliveira26–Reference Schwartz, Boulware and Lee28}

The increased use of broad-spectrum antimicrobials at the start of the pandemic led antimicrobial stewardship teams in our hospitals to create COVID-19 antibiotic guidance that recommended use of empiric antibiotics only for patients with critical illness and a high suspicion of bacterial superinfection, use of short-course antibiotic duration of 5 days for patients with suspected bacterial pneumonia, and antibiotic de-escalation based on microbiological culture results. ^{Reference Barlam, Al Mohajer and Al-Tawfiq29} Although this guidance likely reduced ceftriaxone and azithromycin use after March 2020, increased use of broad-spectrum antibacterial agents in COVID-19 patients persisted. This was likely driven by the poor outcomes of COVID-19 patients before the delivery of vaccines and effective therapeutics. ^{Reference Vaughn, Gandhi and Petty11–Reference Garcia-Vidal, Sanjuan and Moreno-Garcia14}

Not all antimicrobials were more frequently used in COVID-19 patients. Facility-wide AU rates for narrow-spectrum β-lactam agents and quinolones were significantly lower in COVID-19 patients compared to non–COVID-19 patients in 2 of 3 hospitals. Narrow-spectrum β-lactam agents such as ampicillin, cefazolin, oxacillin, and penicillin G tend to be used more for culture-directed therapy. ^{Reference Fernandez-Hidalgo, Almirante and Gavalda30–Reference Wo, Dubrovskaya, Siegfried, Papadopoulos and Jen32} Their less frequent use in COVID-19 patients might reflect fewer culture-proven infections with bacteria (eg, enterococci, staphylococci, and streptococci) for which these agents are commonly used. Quinolones are subject to prospective audit and feedback in our hospitals, and they are often used for culture-directed urinary tract infection treatment, as well as prophylactic antimicrobial therapy in the setting of neutropenia. ^{Reference Marek, Zurek and Degenhardt33} Their less frequent use in COVID-19 patients might indicate a lower proportion of these indications in COVID-19 patients compared to non–COVID-19 patients, coupled with the audit and feedback that comes with their prescription that might prevent their administration for empiric purposes.

Hospital A was different from hospitals B and C in that it did not have greater AU for all antibacterial agents in COVID-19 patients compared to non–COVID-19 patients from both 2019 and 2020. Hospital A had markedly lower AU of narrow-spectrum β-lactam agents, which offset the increase in AU for broad-spectrum antibacterial agents used for hospital-onset infections. In contrast, hospital B had greater AU for broad-spectrum antibacterial agents used for hospital-onset infections without lower AU for other antibacterial classes, and hospital C had greater AU for broad-spectrum antibacterial agents used for hospital-onset infections and community-acquired infections that was not entirely offset by lower AU for narrow-spectrum β-lactam agents. Reasons for this heterogeneity could not be inferred from the data available in this study, but this trend may relate to differences in hospital operations, characteristics, and patient populations.

Facility-wide AU rates for all antibacterial agents, broad-spectrum antibacterial agents predominantly used for hospital-onset infections as specified by NHSN, broad-spectrum antibacterial agents predominantly used for community-acquired infections as specified by NHSN, aminoglycosides, carbapenems, quinolones, and vancomycin were significantly lower in non–COVID-19 patients from March to December 2020 compared to non–COVID-19 patients from March to December 2019 in at least 2 of 3 hospitals. This trend likely reflected changes in the inpatient population. Elective procedures were deferred, admissions for less critical illnesses were reduced, and the most chronically ill patients who ordinarily would have been admitted for non–COVID-19 indications may instead have been admitted with COVID-19. ^{Reference Baum and Schwartz34} Moreover, lockdowns led to a decrease in influenza which may have led to less bacterial superinfection requiring hospital admission. ^{Reference Olsen, Azziz-Baumgartner and Budd35}

The strengths of our study include the development of queries to output AU in COVID-19 and non–COVID-19 inpatients using only electronic data, and its application across 3 hospitals sharing a common data model that resulted in knowledge regarding AU in COVID-19 and non–COVID-19 patients. However, this study had several limitations. First, we did not capture clinical scenarios associated with antimicrobial administration nor did we examine admission or discharge diagnoses for patients. Therefore, we were unable to analyze patient-level factors associated with antimicrobial administration or examine changes in patient types at the onset of the pandemic. However, to our knowledge, this is the first study to examine population-level AU based on NHSN metrics in inpatients stratified by COVID-19 status. Second, we did not correct P values for multiple comparisons because we did not want to increase the chance of making type 2 errors when attempting to minimize type 1 errors. ^{Reference Feise36} However, we were hypothesis-driven and the most germane AU comparisons numbered only 9 across 3 hospitals. Moreover, the difference in AU rates for broad-spectrum antibacterial agents used for hospital-onset infections between COVID-19 and non–COVID-19 patients was large, reducing the likelihood of a type 1 error. Third, we refresh our CAPriCORN databases only every 6 months, which means that we cannot provide real-time information to stewardship teams, only retrospective information. However, the information yielded by our queries can be reviewed twice a year and is actionable on a programmatic level. Fourth, this was a 3-center study in a single metropolitan area in the United States, and these findings may not be generalizable. However, the queries developed in this study can be run in other medical centers participating in PCORnet provided they also populate ancillary tables on bed information. ^{Reference Patel, Santos and Price18} This research would yield national data on AU in COVID-19 and non–COVID-19 patients and has the potential to be updated on a periodic basis.

In summary, the increased use of broad-spectrum antibacterial agents at the onset of the pandemic was isolated to COVID-19 patients. In contrast, the facility-wide AU rate for all antibacterial agents was lower in non–COVID-19 patients in the COVID-19 period compared to non–COVID-19 patients in the pre–COVID-19 period. These findings suggest that antimicrobial stewardship program effects were durable despite the focus on COVID-19 patients, but prescribers had likely not yet adapted to the complexities of COVID-19 management in the setting of poor outcomes early in the pandemic. Tracking AU in COVID-19 patients may help antimicrobial stewardship programs in providing feedback and education to healthcare providers caring for patients with COVID-19, especially now that it has reached endemic status. ^{Reference Barouch37} Advances in diagnostic testing to identify bacterial superinfection would contribute greatly to optimizing AU.