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Clinical Context

Antimicrobial stewardship has not always been top-of-mind during the COVID-19 pandemic, and the authors of the current study described the different forces affecting antimicrobial prescribing from 2020 to the present time. Early reports from China at the outset of the pandemic conveyed that up to half of all deaths related to COVID-19 were due to secondary infection; however, subsequent studies found rates of co-infection of SARS-CoV-2, the virus that causes COVID-19, with other organisms in 3.5% of hospitalized patients, and 14.3% of these patients developed secondary infections.

Of course, the high risk for hospitalization and mortality and lack of clear guidelines or treatment alternatives for the management of COVID-19 also contributed to antimicrobial overuse, but the authors of the current review noted that this phenomenon was most prevalent early in the pandemic and faded with time. The effect of COVID-19 on antimicrobial resistance patterns is largely unknown.

The current study by Khan and colleagues provides a review of research into the use of antimicrobial drugs during the COVID-19 pandemic.

Study Synopsis and Perspective

A statement by the Society for Healthcare Epidemiology of America (SHEA), published online on September 14 in Infection Control & Hospital Epidemiology,^[1] offers healthcare providers guidelines on how to prevent inappropriate antibiotic use in future pandemics and avoid some of the negative scenarios that have been seen with COVID-19.

According to the US Centers of Disease Control and Prevention (CDC),^[2] the COVID-19 pandemic brought an alarming increase in antimicrobial resistance in hospitals, with infections and deaths caused by resistant bacteria and fungi going up by 15%. For some pathogens, such as the Carbapenem-resistant Acinetobacter, that number is now as high as 78%.

The culprit might be the widespread antibiotic overprescription during the current pandemic. A 2022 meta-analysis^[3] revealed that in high-income countries, 58% of patients with COVID-19 were given antibiotics, whereas in lower- and middle-income countries, 89% of patients were put on such drugs. Some hospitals in Europe^[4] and the United States^[5] reported similarly elevated numbers, sometimes approaching 100%.

"We've lost control," Natasha Pettit, PharmD, pharmacy director at University of Chicago Medicine, told Medscape Medical News. Pettit was not involved in the SHEA study.

"Even if CDC didn't come out with that data I can tell you right now, more of my time is spent trying to figure out how to manage these multi-drug-resistant infections, and we are running out of options for these patients," added Pettit.

"Dealing with uncertainty, exhaustion, critical illness in often young, otherwise healthy patients, meant doctors wanted to do something for their patients," said Tamar Barlam, MD, an infectious diseases expert at the Boston Medical Center who led the development of the SHEA white paper, in an interview with Medscape Medical News.

That something often was a prescription for antibiotics, even without a clear indication that they were actually needed. A British study^[6] revealed that in times of pandemic uncertainty, physicians often reached for antibiotics "just in case" and referred to conservative prescribing as "bravery."

Studies have shown, however, that bacterial co-infections in COVID-19 are rare. A 2020 meta-analysis^[7] of 24 studies concluded that only 3.5% of patients had a bacterial co-infection on presentation, and 14.3% had a secondary infection. Similar patterns had previously been observed in other viral outbreaks. Research on MERS-CoV,^[8] for example, documented only 1% of patients with a bacterial co-infection on admission. During the 2009 H1N1 influenza pandemic, that number was 12% of non-intensive care unit (ICU) hospitalized patients.

Yet, according to Pettit, even when such data became available, it did not necessarily change prescribing patterns.

"Information was coming at us so quickly, I think the providers didn't have a moment to see the data, to understand what it meant for their prescribing. Having external guidance earlier on would have been hugely helpful," she told Medscape Medical News.

That is where the newly published SHEA statement comes in: It outlines recommendations on when to prescribe antibiotics during a respiratory viral pandemic, what tests to order, and when to deescalate or discontinue the treatment. These recommendations include, for instance, advice to not trust inflammatory markers as reliable indicators of bacterial or fungal infection and to not use procalcitonin routinely to aid in the decision to initiate antibiotics.

According to Barlam, one of the crucial lessons here is that if physicians see patients with symptoms that are consistent with the current pandemic, they should trust their own impressions and avoid reaching for antimicrobials "just in case."

Another important lesson is that antibiotic stewardship programs have a huge role to play during pandemics. They should monitor prescribing and also compile new information on bacterial co-infections as it gets released and make sure it reaches the physicians in a clear form.

Evidence suggests that such programs and guidelines do work to limit unnecessary antibiotic use. In one medical center in Chicago, for example, before recommendations on when to initiate and discontinue antimicrobials were released, over 74% of patients with COVID-19 received antibiotics. After guidelines were put in place, the use of such drugs fell to 42%.

Pettit believes, however, that it is important not to leave each medical center to its own devices.

"Hindsight is always twenty-twenty," she said, "but I think It would be great that if we start hearing about a pathogen that might lead to another pandemic, we should have a mechanism in place to call together an expert body to get guidance for how antimicrobial stewardship programs should get involved."

One of the authors of the SHEA statement, Susan Seo, reports an investigator-initiated Merck & Co., Inc. grant on cost-effectiveness of letermovir in patients with hematopoietic stem cell transplant. Another author, Graeme Forrest, reports a clinical study grant from Regeneron Pharmaceuticals, Inc. for inpatient monoclonals against SARS-CoV-2. All other authors report no conflicts of interest. The study was independently supported.

Study Highlights

• Researchers searched for studies that included ≥ 50 patients with laboratory-confirmed COVID-19. All studies had to include a focus on antimicrobial use.
• The main study outcome was the trend in antimicrobial use during the pandemic. The research team performed a subanalysis to compare this outcome in high- and middle-/low-income countries.
• The initial search yielded 1671 articles, and 43 underwent complete analysis. 33 studies were completed in high-income countries, and 34 studies focused on hospital or other secondary-care services.
• 35 studies were judged to be of satisfactory or good quality.
• 2 studies that compared the use of antimicrobial drugs in the United States in early 2020 vs previous years found conflicting results. In one study, there was little change in the use of antimicrobials during the pandemic. In the other study, antimicrobial prescriptions actually declined.
• In contrast, several studies from Europe demonstrated that antimicrobial use increased in 2020 vs previous years: 23% of antimicrobial prescriptions were judged to be inappropriate in one study.
• In a study from Pakistan, 88% of antimicrobial prescriptions were not preceded by any testing for pathogens. Unsurprisingly, the pandemic was associated with higher rates of antimicrobial prescribing there.
• 27 studies provided data for a meta-analysis of the overall rate of antimicrobial use during infection with SARS-CoV-2, the virus that causes COVID-19; 68% of patients with COVID-19 were prescribed antimicrobial drugs.
• There was a profound difference in overall antimicrobial use in comparing high-income countries (58%) and middle-/low-income countries (89%).
• The most commonly prescribed antimicrobials among patients with COVID-19 included ceftriaxone, azithromycin, and piperacillin-tazobactam. Azithromycin use was particularly common at the outset of the pandemic.

Figure. Use of Antimicrobial Agents During Infection With COVID-19

Clinical Implications

• Early reports from China at the outset of the pandemic described that up to half of all deaths related to COVID-19 were due to secondary infection; however, subsequent studies found rates of bacterial co-infection of COVID-19 in 3.5% of hospitalized patients, and 14.3% of these patients developed secondary infections.
• The current meta-analysis by Khan and colleagues found that 68% of patients with COVID-19 received antimicrobial drugs. This difference was particularly marked in middle-/low-income countries. The most commonly prescribed antimicrobials among patients with COVID-19 included ceftriaxone, azithromycin, and piperacillin-tazobactam.

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