Growing evidence suggests that, as the Covid-19 pandemic moves across the world, it may drag a second slow-motion pandemic behind it. Even though Covid-19 is a viral illness not affected by antibiotics, early data from hospitals shows that very high proportions of patients—more than 90 percent in some cohorts—are being treated with those drugs to cure or protect against secondary infections during respiratory illnesses or hospitalization. That’s being accompanied by an unmeasured but possibly huge number of people taking antibiotics on their own, or with the encouragement of fringe researchers, in misguided attempts to protect themselves.
Those parallel phenomena mean that Covid-19 could whomp up antibiotic resistance, pathogens’ adaptive ability to defend themselves against drugs intended to kill them. Resistance is already a crisis: It causes an estimated 700,000 deaths around the world each year, almost four times the death toll from the novel coronavirus so far. Diminishing the power of antibiotics could undermine an important part of the medical response to Covid-19.
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A further complication: If increases in resistance occur, there won’t be drugs to fix the problem. Antibiotic manufacturers have been abandoning the market, and some have gone bankrupt, because resistance causes their products to become less lucrative. With drug companies pivoting to searching for coronavirus treatments, there’s a real risk that research into new antibiotics could fall years behind.
“The use of antibiotics anywhere contributes to the emergence of resistance everywhere,” says Kathy Talkington, director of the antibiotic resistance project at the Pew Charitable Trusts. “What we are hearing anecdotally is that more and more antibiotics are being used in this pandemic—and you can imagine that if they are being used more in the United States, then other countries facing the challenge of how to best address Covid-19 are ramping up as well.”
A subtle sign of the growing concern over this is that, in the past month, a number of prominent antibiotic resistance researchers placed op-eds in publications in several countries, in what they say is not a coordinated campaign but an organic expression of how worried these trends make them. The pleas have appeared in magazines, newspapers, trade publications, on the sites of nonprofit organizations, and in personal blogs.
What may have been the first was published on March 23 by Julie L. Gerberding, a physician who was director of the US Centers for Disease Control and Prevention during the George W. Bush administration and now is the chief patient officer and an executive vice president at Merck. She wrote: “The challenge of antibiotic resistance could become an enormous force of additional sickness and death across our health system as the toll of coronavirus pneumonia stretches critical care units beyond their capacity.”
The researchers who are writing these pieces say they felt the need to nudge the problem into public attention now, while governments are debating stimulus spending that could steer some financial support to antibiotics makers. Securing the antibiotic pipeline, they say, is as important in defending against the coronavirus as finding treatments and vaccines.
“In the context of Covid-19, antibiotics should be considered as important as protective gowns or facemasks,” says Adam Roberts, a microbiologist and antibiotic discoverer at the Liverpool School of Tropical Medicine. “We do not expect healthcare workers to go into hospital situations without the correct protective equipment. Nor should we expect clinics to do their job without the appropriate antibiotics. It is part of our defense for any pandemic situation.”
Pneumonia caused by a bacterial infection is an old fellow-traveler to viral pandemics. In 2008 scientists reviewed a raft of scientific literature from the 1918 flu, and also reexamined tissue samples stored from autopsies done during that outbreak. They concluded that “the vast majority” of the possibly 100 million deaths in 1918-19 were caused not by influenza, but by a bacterial infection taking hold in lung tissue that had been traumatized by the flu virus. (The authors included Jeffery Taubenberger, a virologist who achieved the extraordinary scientific feat of recovering the 1918 virus from autopsy samples, and Anthony Fauci, the physician who directs the National Institute of Allergy and Infectious Diseases and has become the science star of the current pandemic.)
One year after that analysis was published, the 2009 H1N1 flu epidemic began. That outbreak was initially considered mild: The World Health Organization estimated at the time that only 18,449 people had died. Researchers at the Centers for Disease Control and Prevention subsequently determined that was a vast undercount, and the death toll was likely 284,000—and a second team of researchers estimated that up to 55 percent of that much larger number of deaths were caused not by the initial assault of the flu, but by a bacterial pneumonia coming along afterward.
The Covid-19 pandemic is still too new to know for certain what proportion of patients develop pneumonias caused by bacteria. But in the papers published so far, there are clues that bacterial infections may be playing as large a role as they did in past pandemics, and therefore might drive increased antibiotic use. One of the first studies outlining what happens to patients in Covid-19 infection, which was published March 11 by physicians in Wuhan, China, described the experience of 191 patients in two hospitals. The physicians found that 15 percent of the patients developed secondary bacterial infections, and half of those who did died.
Roberts and friends have just stood up a site on which they are collecting any new scientific papers that discuss secondary bacterial or fungal infections or antibiotic use in Covid-19. As of Wednesday morning, they had identified 22 peer-reviewed papers and three preprints. A sample of what they’ve found: In Paris, 33 percent of Covid-19 patients were also infected with aspergillus, a frequently drug-resistant fungus that takes hold in people with compromised immune systems; in a separate small study of French patients, one out of five had bacteria and fungi in his lungs. In one set of Chinese patients, 27 percent had a secondary bacterial infection; in another cohort, what authors described as “a large proportion” did.
More worryingly, the papers show that very high proportions of patients hospitalized with what is presumed to be Covid-19 are receiving antibiotics, not to treat diagnosed bacterial infections but as insurance and protection once they are admitted to intensive care units or put on ventilators. In that first Chinese cohort, 95 percent of the patients received antibiotics. In other papers Roberts and team have collected, the proportions are just as high, with 100 percent, 98.5 percent, 93 percent, 89 percent, 64 percent, 58 percent and 45 percent of sets of patients in various places receiving antibiotics as part of their Covid-19 care.
In normal times, those rates would be unthinkably high. Physicians and hospitals try to stick to a set of practices, broadly known as antibiotic stewardship, that are meant to confine antibiotic use to when the drugs are really needed. A key principle of stewardship is making sure that the infections a patient is experiencing are identified and lab-confirmed. That way, physicians can fit the choice and dose of antibiotic to the pathogen infecting a patient and to any resistance that is already present.
It is not routine practice to give antibiotics simply because someone has been placed on a ventilator. But in Covid-19 care, diagnostic procedures that would justify antibiotics—such as snaking a tube into the lungs for a visual exam or retrieving samples of lung fluid—expose health care workers to too much risk. That means no samples to send to the clinical microbiology lab, to determine whether bacteria and fungi are present alongside the virus. And that may lead physicians to prescribe empirically and just in case.
“It worries me that we could end up with loosening of stewardship practices, and a lot of broad-spectrum antibiotic use beyond what we usually have,” says Cornelius J. Clancy, an infectious-disease physician who researches antibiotic use patterns. “And that could be exacerbated by shortages, or supply issues from different parts of the world.”
Stack this concern about extra hospital use, and the resistance it will likely provoke, on top of uncontrolled community use. The antibiotic azithromycin is half of the indie preventive treatment (along with hydroxychloroquine) that was promoted by a physician in France, took off across Silicon Valley, and was pushed relentlessly by the White House and Fox News. There is little evidence this combo works: Just this week, a new preprint study from researchers at the Columbia VA Health Care System in South Carolina, the University of South Carolina and the University of Virginia showed that hydroxychloroquine not only doesn’t protect against Covid-19, but is associated with higher rates of death. (This study is considered preliminary: As a preprint, it has not yet been through peer review or published in a medical journal.)
Nevertheless, according to the Food and Drug Administration, there has been such a spike in azithromycin use that nine different manufacturers have reported shortages they cannot resolve for months.
Azithromycin isn’t the only antibiotic being put to nonstandard use for Covid-19. New papers and preprints show that physicians are experimenting with amoxicillin, tetracycline, doxycycline, and teicoplanin, a last-resort drug used against MRSA, to try to prevent coronavirus infections. That all adds up to vast amounts of excess use, and to enhanced risks of resistance emerging and undermining the power of those drugs.
That’s a problem, because resistance is already potent: In parts of the US, the major bacterial cause of pneumonia defeats the first-choice antibiotic used for it more than half the time. It’s equally a problem because so few new drugs are available to replace them. Last week, the Pew Trusts released new data showing that antibiotic development is fragile: More than half of the new drugs in the pipeline are still in Phase 1 or 2 trials, putting them years from approval. All but one of the firms developing new drugs are small biotechs with little cash on hand to survive the time it will take to get there.
“We don’t have the variety of antibiotics we need, we don’t have the novelty of mechanisms we need, we don’t have enough addressing the World Health Organization’s priority pathogens,” Talkington says.
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No one is arguing that antibiotics should be withheld from patients who need them. (Though dialing down outside-hospital use by the worried well who are using them as a preventative would be a good thing.) The problem instead is how to strengthen drug development so that new antibiotics are available if increased use pushes resistance to new heights. That’s proved a challenge so far.
In addition to its sky-high annual death toll, antibiotic resistance incurs enormous costs: The CDC estimated in 2013 that resistant bacteria require the US alone to spend $20 billion extra on healthcare each year. Yet the problem hasn’t sparked the public policy response that the new coronavirus has. In fact, one bipartisan proposal to get a small amount of additional funding to drugmakers, by increasing the Medicare reimbursement rates of hospital antibiotic purchases, was taken out of the first pandemic stimulus bill.
Just last year, two promising antibiotic companies, Melinta Therapeutics and Achaogen, entered bankruptcy despite having gotten their drugs through the FDA. Since 2000, most of the big legacy drug firms that once made antibiotics have stopped. If coronavirus care makes resistance worse, taking more antibiotics out of circulation, that could encourage the few remaining firms to leave.
The vast international mobilization to do something about the new coronavirus—identify existing drugs, work up new treatments, achieve a vaccine—might paradoxically offer hope for antibiotic research. The enormous amount of work being launched shows that money and purpose can be marshalled against a threat, if the threat seems dire enough. In 2014, a UK government report predicted that deaths from antibiotic resistance could reach 10 million per year worldwide by 2050. That certainly seems dire.
“I’m hoping that once we get out of this, we’ll have a new appreciation of how vulnerable we are to infections, whether that’s new viruses or bacterial infections or resistant fungi on a cancer ward,” says Gerry Wright, a microbiologist and drug discoverer, and director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University, “and that we really need to invest in new drugs and vaccines in advance, and that policy makers will hear that and take some action.”
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