Antibiotics Aimed at COVID-19 Are Escalating Another Threat

Marcia Frellick

March 16, 2021

In the midst of the COVID-19 pandemic, a twin threat looms, affecting someone in the United States every 11 seconds and leading to a death every 15 minutes, according to the Centers for Disease Control and Prevention (CDC).

Antibiotic-resistant infections are on the rise, although they pale in comparison to COVID-19 deaths, which have now hit 535,000 in the United States. But the fear is that what has, in some cases, been overtreatment of COVID-19 might make the problem of antibiotic resistance even worse.

Public awareness of the urgency of the antibiotic-resistance threat is low, says Paul Auwaerter, MD, clinical director of the division of infectious diseases at Johns Hopkins School of Medicine in Baltimore.

Although a large number of Americans have experienced a COVID-19 death in their circle of family and friends or have seen reports of suffering in the media, few have witnessed a death that happened because there was no drug to treat someone's infection.

Paul Auwaerter

"What we most fear is that routine things that we take for granted now — giving chemotherapy to cancer patients, replacing knee joints, having a cesarean section, and not having that complicated by infection — will become much harder or perhaps impossible to manage," Auwaerter says.

Worldwide, superbugs could kill 10 million people annually by 2050 if better treatments aren't developed, according to a United Nations report. The World Health Organization has declared antimicrobial resistance to be among the 10 top threats facing humanity.

The pandemic came on top of an already troubling trend. Even before case counts started to rise, one in three antibiotic prescriptions was found to be unnecessary, according to the CDC.

And then COVID-19 created the "perfect storm" for antibiotic-resistant infections in healthcare settings, another CDC report shows, with prolonged hospital stays, increased antibiotic use, crowding, and severe sickness.

In the early days of the pandemic, amid symptom confusion and desperation with mounting deaths, clinicians were prescribing broad-spectrum antibiotics at unnecessarily high rates, according to Christine Kubin, PharmD, clinical pharmacy manager and lead for infectious diseases and antimicrobial stewardship at NewYork-Presbyterian Hospital, and her colleagues.

When cases surged in New York City in late March and early April last year, about 1700 people were hospitalized each day and approximately 70% of patients with COVID-19 received an antibiotic, the team writes in their recent report, published in the American Journal of Health-System Pharmacy

Christine Kubin

However, patients with COVID-19 had low rates of bacterial coinfection — only about 3% to 8% at the time of admission — they note. That was different from people admitted for influenza, who had bacterial coinfection rates of 11% to 35%.

"This hit us hard and hit us fast," says Kubin.

At the height of the pandemic, "it was really difficult, with the paucity of information, for us to curb antibiotic use from the perspective of these patients, who were critically ill," she explains. "They had a lot of inflammatory markers that we're used to correlating with infection, but in reality, it was part of COVID and part of the hyperinflammatory syndrome, so it was difficult for us to differentiate bacterial and viral infections."

Problems distinguishing illnesses during the pandemic have also been an issue across the nation, including at the University of Wisconsin in Madison, where David Andes, MD, is head of the Department of Infectious Diseases.

David Andes

"The problem is that our diagnostic capabilities to detect these nosocomial bacterial and fungal infections have their own limitations, and with these patients being so ill, even despite negative microbiologic tests, it's not uncommon for clinicians to err on the side of overtreatment," he tells Medscape Medical News.

"We're still learning how to manage these patients who are coming in, from an antimicrobial-stewardship standpoint," he says. "It's been quite challenging."

In addition, resources during the pandemic have been funneled to the prevention and treatment of daily cases of COVID-19, pausing some antimicrobial-stewardship programs.

COVID-19 is such an acute scenario it is impossible to ignore, whereas antimicrobial resistance is a slow and steady, yet progressive, phenomenon.

Complications from COVID are coupled with a decades-long development drought for new antibiotics and a dysfunctional market that discourages the production of new antibiotics.

Development Roadblocks

Experts agree that overprescription is only part of the problem, and that pipeline and market issues must be resolved to stave off antibiotic resistance.

David Hyun

"We haven't had a truly new class of antibiotics developed and brought to market in 35 years now," says David Hyun, MD, director of the antibiotic-resistance project at Pew Charitable Trusts.

The last nine antibiotics were approved — three each year — in 2017, 2018, and 2019, according to a spokesperson for the US Food and Drug Administration (FDA).

But recently approved drugs are hybrids from scientific discoveries made before 1984, Hyun tells Medscape Medical News. And mixing and matching opens the door for cross-resistance, which is another reason brand new antibiotic classes are needed, he explains.

Big pharmaceutical companies have pulled out of antibiotic development, leaving the job to small biotech companies. But the current model is not sustainable and many have declared bankruptcy.

From 2014 to 2020, the number of large pharmaceutical companies developing new antibiotics fell from eight to two, according to a report from Pew Charitable Trusts.

"They're not able to recoup the investment in costs," Hyun says. Much of that has to do with the short duration of use for the inexpensive drugs — usually less than 2 weeks — as opposed to that for cancer or chronic diseases, such as diabetes, which are much more lucrative. Also, physicians try to use antibiotics as a last resort, for stewardship purposes, which runs against market goals.

In 2019, $9.7 billion in private investment went into oncology research, compared with just $132 million for antibiotics research, Pew reports.

According to a new report from Pew, as of December 2020, 43 antibiotics were in development: 15 in phase 1 clinical trials, 13 in phase 2 trials, 13 in phase 3 trials, and two awaiting word from the FDA on New Drug Application status.

"Historically, about 60% of drugs that enter phase 3 will be approved," the Pew report says.

A pharmaceutical collaboration — the AMR Action Fund, announced in July 2020 — is among the new approaches to speed development. More than 20 pharmaceutical giants have pledged to invest more than $1 billion in smaller biotech companies to bring two to four new antibiotics to patients by 2030.

Although this is a welcome development, even the stakeholders acknowledge that it is a temporary solution, says Hyun.

Meanwhile, the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance, or PASTEUR Act, supported by Pew, is awaiting reintroduction in the new Congress.

It would allow the federal government to contract with antibiotic innovators in a "Netflix-type" subscription model. Under that model, financial stability for innovators would no longer be based on use or sales of the individual drugs. Instead, a subscription model would provide a predictable return on investment for new antibiotics.

The PASTEUR legislation remains a high priority for the Infectious Disease Society of America (IDSA), and "we are eager for its reintroduction this year," says Amanda Jezek, senior vice president for public policy and government relations at IDSA.

"The COVID-19 pandemic has demonstrated the importance of preparedness, and an arsenal of safe and effective antibiotics is a critical tool in responding to public health emergencies, many of which can be complicated by secondary resistant infections," she tells Medscape Medical News.

In the meantime, the healthcare system has to remain vigilant about antimicrobial stewardship.

Lessons From New York City

In their analysis of data from New York City, Kubin and her colleagues describe how their antimicrobial-stewardship program overcame obstacles.

Pharmacists were embedded in front-line units to disseminate information. With the COVID-19 crisis, "no one's reading their emails, so as much face time as possible" is necessary, Kubin explains.

In addition, multidisciplinary teams should "find a time to meet on a daily or weekly basis to share the most pertinent information," she advises.

Kubin's team had a few people dedicated to combing through the literature and sharing information with a multidisciplinary group so that they could develop hospital guidelines "almost weekly."

Plus, experience and education have given prescribers confidence over the past year. "We're definitely much more comfortable withholding antibiotics for bacterial infection in these patients without the evidence of a bacterial infection going on," Kubin says.

Marcia Frellick is a freelance journalist based in Chicago . She has previously written for the Chicago Tribune and Nurse.com and was an editor at the Chicago Sun-Times, the Cincinnati Enquirer, and the St. Cloud ( Minnesota ) Times. Follow her on Twitter at @mfrellick.

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