Issue No. 62: The Right Way to Fight Superbugs

With COVID 19, Americans have learned just how dangerous the spread of pathogens can be. There is another health threat that needs addressing before it’s too late: antimicrobial resistance, or AMR. Over the years, bacteria, fungi and other microorganisms mutate and find ways to survive against medicines meant to attack them. “Unfortunately, resistance has been seen to nearly all antibiotics that have been developed,” writes C. Lee Ventola in a paper titled, “The Antibiotic Resistance Crisis,” in the journal Pharmacy and Therapeutics. “As a result, says the World Health Organization, “the medicines become ineffective and infections persist in the body, increasing the spread to others.”

Concludes a World Bank study: “If this trend continues unchecked, the world will confront a reality where many infectious diseases have ‘no cure and no vaccine.’”

Microorganisms that develop effective resistance are nicknamed “superbugs,” and they can be fatal. According to a report last year by the Centers for Disease Control (CDC), “More than 2.8 million antibiotic-resistant infections occur in the United States each year, and more than 35,000 people die as a result.” Deaths worldwide are estimated at 700,000, and if current trends continue, AMR will be the leading global cause of death by 2050, killing 10 million and reducing the world’s GDP by 2.2%, according to the Review on Antimicrobial Resistance, also called the O’Neill report.

The World Bank study, published in 2017, found that under a “pessimistic high-AMR scenario, global economic output would be 3.2 percent lower in 2030 and then fall further, so that in 2050, the world would lose 3.8 percent of its GDP, relative to the base case.”

Economic Costs of AMR May Be as Severe as During the Financial Crisis

Source: World Bank Group, “Drug-Resistant Infections: A Threat to Our Economic Future,” March 2017.

​Currently, due to unique challenges facing new antibiotics that we will describe below, too few pharmaceutical researchers are working to develop new antibiotics to overcome AMR, but, with good policies, a dire situation can change, as we will see.

Antibiotic Resistant Bacteria and COVID 19

We expect that the COVID-19 crisis has exacerbated the AMR crisis. “It is of the utmost importance that the potential of the global pandemic to increase antimicrobial resistance (AMR) is taken seriously,” said an editorial in the journal Nature on May 20, adding….

A peek under the hood of studies reporting on patients hospitalized with coronavirus disease 2019 (COVID-19) reveals widespread use of antimicrobial therapies as part of the package of clinical care in some countries. For example, in a retrospective cohort analysis of 191 patients from two hospitals in Wuhan, Zhou et al. write that 95% of patients were treated with antibiotics and 21% were treated with antivirals.

Antibiotics work against bacteria, and they are useless against a virus like SARS-CoV-2, the cause of COVID-19. But a virus can unleash secondary bacterial infections. A Bloomberg article on March 8 explained one way in which COVID-19 kills:

The lungs are vulnerable to an invasive secondary bacterial infection. Potential culprits include the germs normally harbored in the nose and throat, and the antibiotic-resistant bacteria that thrive in hospitals, especially in the moist environments of mechanical ventilators. Secondary bacterial infections represent an especially pernicious threat because they can kill the critical respiratory tract stem cells that enable tissue to rejuvenate….

During the 1918 pandemic of Spanish flu, which killed an estimated 50 million people worldwide, including 675,000 in the United States, "the majority of deaths...likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria,” according to a study in the Journal of Infectious Diseases co-authored by scientists Tony Fauci, David Morens, and Jeffrey Taubenberger, of the National Institute of Allergy and Infectious Diseases. At the time, of course, there were no antibiotics to combat the bacteria.

It is now becoming clear, however, that fears of bacterial infections resulting from COVID have been overblown. SARS-CoV-2, the virus the world is now facing, is not the Spanish flu. Certainly, some patients do acquire bacterial coinfections (often from the hospital environment itself), and for them, antibiotic treatment is appropriate, says the Nature editorial.

“But these patients may be in a minority,” the editorial continued. “Writing in Clinical Microbiology and Infection, a group of European clinicians admit that it can be difficult to differentiate COVID-19 from bacterial pneumonia, which means that some patients without bacterial infections are receiving unnecessary antibiotics.”

A New York Times article by Andrew Jacobs on June 4 carried the headline, “Doctors Heavily Overprescribed Antibiotics Early in the Pandemic.” It quoted the director of epidemiology and antibiotic stewardship at the Detroit Medical Center as saying, “During the peak surge, our antibiotic use was off the charts.” Antibiotics were being administered to 80% of arriving patients. It became clear that this was a mistake, Dr. Chopra said.

“Nearly all severe COVID-19 patients” in the U.K. were being “treated with antibiotics, which may have limited efficacy,” wrote Jose Bengoechea and Connor Bamford of the Wellcome-Wolfson Institute for Experimental Medicine in the journal EMBO Molecular Medicine. They added….

Unfortunately, as the pandemic continues, we anticipate a significant increase in AMR through the heavy use of antibiotics in COVID‐19 patients. Even in a normal scenario, ICUs are epicentres for AMR development. This may have devastating consequences in those hospital settings with already a high prevalence of multidrug‐resistant strains. It is evident that as SARS‐CoV‐2 is transmitting in hospitals, also multidrug‐resistant bacteria are, leading to an increase in the mortality due to the limited arsenal of antibiotics to treat hospital‐acquired infections.

As Tedros Adhanom, the director general of the World Health Organization, noted, “COVID-19 has led to an increased use of antibiotics, which ultimately will lead to higher bacterial resistance rates that will impact the burden of disease and deaths during the pandemic and beyond.”

Unless we seriously tackle the AMR threat, we could arrive soon at time when antibiotics – miracle drugs that have saved hundreds of millions of lives -- won’t work.

The Vanishing Promise of Antibiotics

Last year’s CDC report, “Antibiotic Resistance Threats in the United States,” begins with the story of a woman named Anne Miller of New Haven in 1942. She was very ill:

Infectious germs had made their way into her bloodstream. Desperate to save her, doctors administered an experimental drug: penicillin, which Alexander Fleming discovered 14 years earlier. In just hours, she recovered, becoming the first person in the world to be saved by an antibiotic. Rather than dying in her thirties, Ms. Miller lived to be 90 years old. Today, decades later, germs like the one that infected Mrs. Miller are becoming resistant to antibiotics.

An antibiotic is a drug to treat bacterial infections, which range from salmonella to syphilis to impetigo to meningitis to pneumonia. Penicillin, developed from a mold, and other early antibiotics were substances produced by one microorganism that inhibits the growth of another. Later, synthetic antibiotics were developed that had the same effects. Antibiotics, most of which are inexpensive generic drugs, save millions of lives around the world each year.

The problem is that germs fight back by altering their composition through mutations, blocking the entry of drugs or developing pumps to get rid of them, and can achieve the “ability to defeat the antibiotics designed to kill them,” says the CDC. Antibiotic resistance “does not mean your body is resistant to antibiotics” but that bacteria and fungus are.

AMR moves fast. Just a decade after penicillin became widespread, “more than half of common Staphylococcus bacteria in big hospitals were resistant to it,” according to an article in The Economist last year. “In response, drug firms churned out new antibiotics at a steady pace to replace ineffective ones. But as the 20th century drew to a close this arms race in antibiotics became harder because of their rampant use worldwide – on humans, livestock and crops.” The more an antibiotic is used, the faster bacteria develop mutations that confer resistance to it.

In its report late last year, the CDC identified five resistant bacteria as “urgent threats,” 11 as “serious threats,” and five more as “concerning” or earning a place on a “watch list.” Among the urgent threats are drug-resistant Candida auris, which causes severe blood-borne infections around the world, and Neisseria gonorrhoeae, which causes 1.1 million sexually transmitted infections a year, half of them drug-resistant. Such popular antibiotics as penicillin, tetracycline and ciprofloxacin are no longer recommended for gonorrhea, which can cause permanent health problems in both men and women.

The CDC calls another of those in the “urgent category,” drug-resistant Acinetobacter, which turned out to be one of the bacteria found in COVID 19 patients, “a challenging threat to hospitalized patients because it frequently contaminates healthcare facility surfaces and shared medical equipment.” The CDC first flagged Acinetobacter in 2013, and cases dropped from 10,300 that year to 8,500 in 2017, mainly because of better hospital practices. Some types of bacteria are resistant to carbapenem, which is usually a highly effective antibiotic class. Unfortunately, “treatment options for infections caused by carbapenem-resistant Acinetobacter baumannii are extremely limited. There are few new drugs in development.”

Where Are the New Drugs?

“Antimicrobial resistance continues to erode our therapeutic armamentarium,” said an editorial last year in the New England Journal of Medicine. So where are the reinforcements? Where are the new antibiotics to replace those that have become ineffective?

The Economist points out that in 1980, there were “25 large pharma companies working on new antibiotics; by 2020, there were just three.”

A paper accepted June 25 by the journal Clinical infectious Diseases by Nidhi Dheman and colleagues notes that the number of investigational new drug (IND) applications to fight bacteria dropped to an 11-year low in 2019, “and the number of antibacterial INDs initiated with the FDA from 2010-2019 was lower than any of the previous three decades.” The paper also points out that while antibacterial drug development programs in the 1980s and 1990s “had high success rates, with over 40% of INDs obtaining marketing approval, in a median time of about six years,” later programs had a success rate of just 23% with development time averaging 8.2 years.

The Pew Charitable Trusts in April found that 41 new antibiotics are currently in clinical development, many of them addressing resistant bacteria. But 41 antibiotics in Phase 1, 2, or 3 of clinical trials is a tiny number in the world of pharmaceutical R&D. Compare it to more than 300 drugs in development for skin diseases and 1,100 for cancer, according to PhRMA.

Why, in the midst of an AMR crisis, are here so few potential new medicines for antibiotics?

On March 18, STAT published an article by Isaac Stoner, a biomedical entrepreneur who in 2018 founded Octagon Therapeutics, focused on producing more effective antibiotics. “It turned out to be a disaster,” Stoner wrote. He and his colleagues had found a powerful new compound they wanted to bring to market. But “investor after investor turned us down. Antibiotics, they said, were practically guaranteed money losers. Sadly, it turns out they are right.” So his company dropped the antibiotic.

Another firm that found trouble was Achaogen, a startup biotech, which in June 2018 gained FDA approval for Zemdri, a treatment for urinary tract infections resistant to multiple antibiotics. Sales were minuscule – less than $1 million the first year. By April, as Wired recounted the story, Achaogen was bankrupt, with $120 million in debt. “Even a company that succeeds in bringing an innovative new antibiotic to market can’t necessarily survive,” said Allen Coukell of Pew, quoted in CIDRAP News.

“I’m worried the remaining small biotech companies won’t be here this time next,” said Greg Frank, director of Working to Fight AMR, an advocacy group. “The longer we wait,” said Frank, quoted by the New York Times, “the deeper in the hole we’re in and the more expensive it’s going to be to solve the problem.”

The economics killing innovation to battle AMR is not intuitive. Consider the usual model of drug development. If there are no drugs that effectively treat a disease, manufacturers have an incentive to develop a new medicine that can. The cost of bringing a single new, approved medicine to market is high – an average of nearly $3 billion – with very few therapies actually successfully making it through the R&D process and receiving FDA approval, but the investment can be justified by the potential prospect of future revenues, especially if a large number of patients needs the drug.

Pricing Divorced From Value

But the market for antibiotics is different. In his first-person story, Stoner explained:

Last-resort antibiotics, the ones that are effective against the most dangerous bacteria, are an option that doctors rarely turn to, prescribing them only in limited emergency scenarios. If such novel antibiotics are overused, bacteria will develop resistance to them. This caution is scientifically sound, but it creates a problem for companies developing new treatments: the number of patients receiving them will — hopefully — always be low.

Stoner also writes that “insurers are incredibly tight-fisted when reimbursing doctors and health systems for their use of antibiotics,” and Medicare pays hospitals the same to treat patients with infections “whether they use cheap generics or more effective — and more expensive — cutting-edge drugs.”
So pricing is divorced from value, and, Stoner concludes:

At current price points, and with responsible prescribing practices, companies developing new and effective antibiotics have no hope of recouping the massive development costs needed to bring them to market.

A 2016 study by Wayne Weingarden of the Pacific Research Institute pointed to two additional obstacles for new antibiotics. First, the drugs “are prescribed for a relatively short period of time – the prescription’s duration is measured in days or weeks, the time it takes to kill the infection, rather than in years as is the case with other potential innovations. The shorter prescription time…limits potential antibiotic sales and consequently potential revenues.” Also, he writes:

The development costs for new antibiotic and antiviral therapies will likely be higher because the clinical trials require a highly selective patient population (e.g. those patients who are afflicted with the resistant microorganisms). There are simply fewer of these patients available, therefore, this requirement makes the clinical trials more difficult to carry out.

Drugs to battle AMR, then, are victims of a kind of market failure. They are expensive to develop, but physicians use them sparingly and insurers deny them the kind of premium they deserve.

Stewardship Strategies

Patient groups, foundations, international organizations, and health care providers, and drug manufacturers have proposed solutions -- some behavioral and informational, some economic. The Davos Declaration, signed by more than 80 companies in 2016, called for, among other measures, stewardship strategies for “ensuring antibiotics are only used by patients who need them” and increased surveillance. A database called ATLAS (Antimicrobial Testing Leadership and Surveillance) was launched by Pfizer in 2017, providing physicians and public health workers with access to data on the efficacy of antibiotic treatments and emerging resistance patterns around the world. Pfizer, Wellcome, and the governments of Ghana, Kenya, Malawi and Uganda announced a partnership last month to provide increased surveillance for data-gathering.

The CDC is working to prevent the number of infections – and thus reduce the need for antibiotics in the first place – by encouraging vaccinations (the PCV13 vaccine, for example, protects against 13 forms of pneumococcus, including resistant ones) and safe-sex practices and by stopping the spread of germs in hospitals and non-hospital institutions, such as nursing homes.

“Greater focus on infection prevention and control, using antibiotics only when needed, as well as innovations in diagnostic testing, alternative treatments, and effective vaccines, will better prepare the United States for the resistance that will continue to emerge worldwide,” said the CDC report.

Economic Solutions

There’s evidence that those steps are working, but it is clear that something more is required: an economic fix. In a letter to Congress, Pew, the Infectious Diseases Society of America, the Trust for America’s Health and 23 other groups called for a “package of economic incentives to reinvigorate the stagnant pipeline of antibiotics.” The letter noted that of antibiotics in development today, only 11 have the potential to address the superbugs that the World Health Organization considers the most dangerous. That is just 11 of the total 7,000 drugs in development for all diseases.

The letter recognized that Congress previously had taken some steps to battle AMR, such as the Generating Antibiotics Incentives Now (GAIN) Act of 2012 “to extend the market exclusivity period for certain antimicrobials and, four years later, creating the Limited Population Antibacterial Drug regulatory approval pathway to facilitate the development of antibiotics and antifungals for patients who have few or no treatment options.”

But those steps, as well as increased funding for NIAID and BARDA to support antibiotic R&D, have not been enough. (Achaogen received help from BARA, the Biomedical Advanced Research and Development Authority, but the company still failed.)

Economic solutions need to address what Seth Seabury and Neeeraz Sood in the Health Affairs Blog call “pull incentives,” that is, “demand-based tools designed to make the market more attractive for a successfully developed product.” New antibiotics “are intended to have limited initial use,” so vast sales are unlikely. What are ideas that can create enough pull to inspire investment in antibiotics?

One popular idea is government payments to companies that successfully develop therapies targeted against the most threatening infections. A discussion guide for a January conference in Washington held by the Duke Margolis Center for Health Policy emphasized the particular value of “post-approval market entry rewards,” or MERs. Said the guide:

According to a thorough literature review and stakeholder analysis conducted by DRIVE-AB, an entry reward is the most commonly recommended potential pull incentive. Such a reward would likely take the form of multiple annual payments to a developer following the approval of a new antimicrobial…to ensure consistent revenue.

Awards, said the O’Neill Commission, “would ‘de-link’ the profitability of a drug from its volume of sales, supporting conservation goals by eliminating the commercial imperative for a drug company to sell new antibiotics in large quantities.”

Sen. Michael Bennet (D-Colo) is sponsoring the PASTEUR (Pioneering Antimicrobial Subscriptions to End Surging Resistance) Act, which sets up an expert committee on Critical Need Microbials to develop a list of microbes for which drugs are needed and to provide subscription contract awards, payable over up to three years, to developers of the drugs.

Another idea is awarding to an antimicrobial innovator a grant of an exclusivity extension that “could be applied to some other, existing drug on a one-time basis,” write Seabury and Sood. The extension would be tradeable, “so an innovator with no existing product could sell the extension to a manufacturer with a drug close to patent expiry.”

Developing Novel Reimbursement Models

Last year, Democratic Sen. Bob Casey of Pennsylvania and Republican Sen. Johnny Isakson of Georgia (who retired in December) introduced the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (or DISARM) Act. DISARM would reimburse novel antibiotics targeted against resistance infections with additional payments to hospitals, helping to drive better access for patients that need these therapies. A separate bill was introduced by a bipartisan group in the House headed by Rep. Danny Davis (D-Ill).

The U.K.’s National Health Service last year launched a pilot program to encourage the use of new antibiotics, paying “pharmaceutical companies up front for access to effective antibiotics, rather than reimbursing them based on the quantity of antibiotics sold…. Under the new model, drug makers would still be reimbursed by the NHS even if the new drugs are kept in reserve.”
 
"Today we are sending a strong signal to the rest of the world that there are workable models to stimulate investment in these vital medicines and that together we can tackle" antimicrobial resistance, Health Minister Nicola Blackwood said. 

The truth is that possible remedies to the AMR crisis abound. Matthew Renwick of the London School of Economics and two colleagues identified 47 different ones in a paper in the Journal of Infectious Diseases in 2016. What is undeniable is that action is required now to prevent million of deaths in the future. Waiting, as we have certainly learned with the current coronavirus pandemic, is not an option.