The Paradox That Haunts New Antibiotics

Forget COVID-19, monkeypox, and other viruses for the moment and consider another threat troubling infectious disease specialists: common urinary tract infections, or UTIs, that lead to emergency room visits and even hospitalizations because of the failure of oral antibiotics.

There is no Operation Warp Speed to save us from these germs, which increased in number during the initial year of the pandemic. This new Centers for Disease Control and Prevention report states. The Food and Drug Administration (FDA), which declined approval of two promising oral medications, sulopenem and Tebipenem, to treat drug-resistant UTIs in the last year, said it required more evidence.

During this time, UTI patients will need to be admitted for IV treatment of a bladder infection. This is in contrast with the usual procedure of treating the patient with oral antibiotics.

Rebecca Clausen was an office worker from Durham in North Carolina who received several doses of an oral antibiotic to treat a persistent UTI. However, it kept coming back. Doctors considered a six-week treatment with an intravenous drug, ertapenem, which would have cost her about $2,000 out-of-pocket, but decided it probably wouldn’t help. Clausen hopes the infection doesn’t get worse.

While specialists claim they’re seeing more cases of UTIs than oral antibiotics, it’s still considered a rare problem (federal officials aren’t able to track this issue). It is emblematic of an industry failure that, according to experts and U.S senators, can only be corrected by government intervention.

The CDC report, released July 12, shows that after mostly declining during the previous decade, the incidence rates of seven deadly antimicrobial-resistant organisms surged by an average 15 percent in hospitals in 2020 because of overuse in COVID-19 patients. The most dramatic growth was seen in insects that are difficult to treat UTIs.

Although nearly 50,000 Americans–and about 1.3 million people worldwide–die of resistant bacterial infections each year, the FDA hasn’t approved a new antibiotic since 2019. Big Pharma has mostly abandoned antibiotics development, and seven of the 12 companies that had successfully brought a drug to market in the past decade have gone bankrupt or have left the antibiotics business because of poor sales.

This is due to a paradox. The faster an antibiotic is used, the more bacteria will evolve to avoid it. So practitioners are aggressively curbing use of the drugs, with 90 percent of U.S. hospitals setting up stewardship programs to limit the use of antibiotics, including new ones. Investors have lost interest in the industry due to this.
A pipeline of drugs for new antibiotics is essential, considering the inexorable ability of bacteria to adapt and mutate. But while resistance is an ever-present danger, some 90 to 95 percent of fatal infections involve microbes that aren’t multidrug-resistant but are difficult to treat for other reasons, such as the delicate condition of the patient, said Dr. Sameer Kadri, head of clinical epidemiology at the National Institutes of Health (NIH) Clinical Center’s Critical Care Medicine Department.

“As harmful as antibiotic resistance can be, it’s only bad for a small number of people,” stated Jason Gallagher , Professor and Infectious Diseases pharmacist at Temple University Hospital. Because clinicians are often unable to quickly identify a bug’s resistance level in a timely manner, most doctors will use the older drug.

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” This makes anti-infectives an expensive investment for drug companies,” he said. You’re going develop your drug and the people will do everything they can to avoid using it .”

As the scientific knowledge of antibiotics companies fades, so do their expertise in science, according to Dr. David Shlaes ,, a former pharmaceutical industry scientist. He said that if a particular deadly resistance pattern develops without any drug pipeline, it can cause massive destruction.

“Antibiotics are an essential part of civilization,” said Kevin Outterson, a Boston University law professor who leads a public-private fund that helps companies develop antimicrobials. They must be renewed each generation otherwise we’ll fall back to the antibiotic era .”

The regulatory and complex issues surrounding antibiotics are illustrated by the roadblocks that prevented the approval of UTI drugs sulopenem and tebipenem from being approved.

In a large clinical trial, Iterum Therapeutics’ sulopenem performed better than ciprofloxacin at relieving UTI symptoms. However, it was not as effective at eliminating bacteria which is an important measure of success. FDA officials suggested that they may be open to changing their standards in the future at a June 3 workshop.

Another company, Spero Therapeutics published what appeared to be a positive trial of oral tebipenem, in the New England Journal of Medicine April. FDA officials denied Spero’s request for licensure, citing that a specific species of bacteria in the study was not relevant to the drug’s effectiveness.

A Lifeline for Patients

Though new oral drugs against UTIs are sorely needed, IV drugs can still conquer most routine UTIs. Patients with chronic, serious diseases such as cancer or severe disabilities are particularly concerned about the possibility of not having new antibiotics in the future.

Two or three times a day, Molly Pam, a 33-year-old chef and patient advocate in San Francisco, inhales nebulized blasts of colistin or aztreonam. These are antibiotics that the typical person stays away from, but for the 30,000 U.S. cystic fibrosis patients such as Pam, deadly bugs and powerful drugs are a fixture of life.

Pam visits a hospital or clinic for IV treatment when she feels sick or has a fever. In 2019, just as she was approaching resistance to all antibiotics, the drug Zerbaxa received FDA approval.

Pseudomonas and MRSA, or methicillin-resistant staphylococcus aureus, bacteria have colonized Pam’s lungs since she was a child, their mutations requiring frequent antibiotic updates. In 2018, she was struck down with a drug-resistant, tuberculosis-like bacteria that required a year of three-times-a-day IV drug treatments on top of her other drugs. After she started coughing up blood, she was flown to Stanford Medical Center.

Doctors examine Pam’s stool four times per year in order to identify any bugs and prescribe antibiotics. There are always a few more mutations that could lead to disaster.

” I absolutely depend on new medicines,” Pam stated.

Steering Stewardship Programs

The development and testing of these new molecules is hardscrabble terrain, featuring frequent conflicts between the FDA and industry over how to measure an antibiotic’s effectiveness–is it patient survival? What is the best way to improve symptoms? Bacteria count? How long?

Meanwhile, Congress has aided the industry with patent extensions, and federal agencies have poured in hundreds of millions of dollars in grants and partnerships. The World Health Organization and the drug industry in 2020 created a $1 billion venture capital fund to support worthy antibiotics companies.

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Stewardship of antibiotics has arguably had the greatest influence on reducing resistance. A 2019 CDC report found an 18 percent reduction since 2013 in deaths caused by drug-resistant organisms, and a 21 percent decline in infections of MRSA, once a leading medical boogeyman.

But it can be harder to test new medicines. Clinical trials of new antibiotics are conducted to determine their efficacy against resistant bacteria. This is because it’s still rare for these infections to be highly resistant.

Because new drugs are often approved simply because they show similar effectiveness to existing drugs, doctors treating infectious diseases tend not to recommend them.

“There aren’t that many people with antibiotic resistance,” said Dr. Emily Spivak, who leads stewardship programs at the University of Utah and Veterans Affairs Salt Lake City hospitals. It’s terrible when people contract these infections. However, there isn’t enough money to generate the profits that companies desire .”

For example, hospitalized patients with MRSA-related pneumonia often can be treated with vancomycin (starting at about $15 per day), said Spivak, who chairs the Infectious Diseases Society of America’s antimicrobial resistance committee. She sometimes turns to a newer alternative, ceftaroline ($400 a day), which can have fewer side effects.

” However, even though we don’t use these drugs often, and will never, there are other ways to avoid MRSA. For example, you can clean your skin prior to surgery, or keep catheters clean .”

Time for ‘Warp Speed’?

In the early days of COVID-19, many hospitals desperately threw antimicrobials at the mysterious virus, and the pandemic crisis strained stewardship teams, Spivak said. The new CDC data show that clinicians gave antibiotics to 80 percent of hospitalized COVID-19 patients in the first eight months of the pandemic, although such drugs have no impact on COVID infection.

But the adoption of new antibiotics is slow. A report on 17 new antibiotics marketed in the United States over the past five years showed only three with sales over $100 million per year. The 17 antibiotics had average sales of about $44 million for the 12 months ending in June 2020.

A few of the new drugs, such as a combination antibiotic marketed in the United States as Avycaz, have gradually replaced colistin, a highly toxic 1950s compound that was brought back in 2000 because of its efficacy against certain resistant bacteria.

Yet, even though that was the recommended method by experts in infectious diseases, it took a while. That isn’t surprising since colistin costs about $140 for a 10-day treatment, while a course of Avycaz might set a hospital back $14,000 to $28,000, noted Dominic Chan, chief of pharmacy services at Legacy Health in Oregon.

Medicare reimbursements for hospital infection treatment are low, Chan stated. “There’s no incentive to the hospitals to spend that kind of capital in bringing these agents into–other than doing what is right .”

In most cases hospitals are doing what is right. Recent CDC data show that 90 percent of U.S. hospitals have stopped using colistin, agency spokesperson Martha Sharan said.

Executives representing the shrinking number of antibiotics manufacturers complain about stewardship programs that are too generous, which is detrimental to patients. Partly, they point to Medicare programs which pay hospitals lump sums for the treatment of certain conditions. A congressional bill filed in 2019 and resubmitted last year would require Medicare to pay for new antibiotics separately. The bill was blocked by Democrats, however antibiotics manufacturers argue that it will incentivize hospitals using their drug.

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Refusing to use the new antibiotics can make resistance worse to older drugs, which “makes it harder for a brand new antibiotic to do their job,” Ted Schroeder (CEO of Nabriva, an antibiotics manufacturer) and head of an industry group said.

But, the bottom line is the majority of patients don’t require the newest drugs.

In a 2020 NIH study that the FDA helped fund, Kadri and his colleagues reviewed records from 134 hospitals from 2009 to 2015 to find examples of difficult-to-treat, highly resistant bacteria of the gram-negative type–a key area of concern. Of about 139,000 gram-negative infections, only 1,352 fell into the difficult-to-treat category–roughly 1 percent.

” There are not enough patients” to make it possible for the market to be able to purchase new anti-biotics, Kadri stated.

Extrapolating from the study, the market for new antibiotics against highly resistant gram-negative bacteria would range from $120 million to $430 million a year, compared with the average $1 billion needed to develop a single drug, wrote Drs. Neil Clancy and Minh-Hong Nguyen of the Veterans Affairs Pittsburgh Healthcare System.

In an absence of viable markets, infectious diseases experts, drug companies and patient groups rallied around the PASTEUR Act introduced by Senators. Michael Bennet (D-Colo.) and Todd Young (R-Ind.) Last year, the bill was introduced by Michael Bennet (D-Colo.) and Todd Young (R.Ind.). The bill would create a fund of up to $11 billion over 10 years to award promising antimicrobials that were close to or had received FDA approval. To eliminate the temptation to overuse, payments would be guaranteed of as much as $3 billion by the government for every drug.

PASTEUR has 40 co-sponsors in the Senate. Experts believe its passage is vital.

“Even though the population is not in dire need of new drugs, it’s still important to have a wide range of options for patients who may need them. You want to be able to access safe, effective drugs if you’re in need.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF, a nonprofit endowed organization that provides information to the nation on health-related issues.

Arthur Allen is a senior correspondent and writes about the FDA and the pharmaceutical industry as well as covid-related topics. This article was originally published on Kaiser Health News.

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