By Michael G. Malloy
When British doctor and scientist Alexander Fleming discovered penicillin in 1928, he recognized that in addition to being a ruthless bacteria killer, the first antibiotic would prompt bacterial “bugs” to mutate over time after being exposed to it—a normal evolutionary response. Fast-forward to nearly 100 years later and a plethora of antibiotics developed since then, and descendent “superbug” bacteria have become resistant to multiple drugs, causing concerns about simple or complex infections wreaking the havoc they once did, when Fleming saw routine infections kill and maim thousands of soldiers in the World War I trenches, where he served as a medic.
Today, “Gram-negative bacteria” are the prime superbug culprits—bacteria with particularly hard outer double-wall structures, and proteins effective at pumping antibiotics out of their cells. In the U.S., such superbugs tend to be the most problematic in hospital settings, where people’s infection rates are higher and immune defenses are lower.
Perhaps the leading voice of U.S. public health for the past few decades, Anthony Fauci, a medical doctor and the longtime head of the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID), said that while superbugs may not be at top of the nation’s health-threat pyramid, the issue is one of growing concern.
“The answer is yes, in some respects,” Fauci said in an interview regarding superbugs being a serious public health issue. “You don’t want people to say it’s as important as the 700,000 people who die from heart disease, or the 400,000 who die from cancer and HIV/AIDS each year, but it is a growing problem that is getting worse over the years. If it really does explode, it can wind up being one of the significant issues we have to deal with.”
According to the U.S. Centers for Disease Control and Prevention (CDC), about 2 million people in the United States get antibiotic-resistant infections each year and at least 23,000 people die from them. While antibiotic resistance threats vary nationwide, they have been found in every state. In its “Vital Signs” publication from April 2018, CDC referenced particularly difficult-to-treat “nightmare bacteria,” noting that lab tests uncovered unusual resistance more than 200 times in Gram-negative strains alone in 2017.[1]
Some reports are even more dire in their assessment. The World Health Organization (WHO), a United Nations (UN)agency, said in April of this year that if no action is taken, drug-resistant diseases could cause 10 million deaths per year by 2050, and that the damage to the global economy could be as catastrophic as the 2008–2009 global financial crisis.[2] By 2030, antimicrobial resistance could force up to 24 million people into extreme poverty, according to the WHO report, issued by the UN Interagency Coordination Group on Antimicrobial Resistance.
Those figures were in line with a 2016 Great Britain-based report by the Review on Antimicrobial Resistance—funded by the U.K. government and the Wellcome Trust—which said that between now and 2050, $100 trillion of economic output could be at risk due to the rise of drug-resistant infections.[3] That report recommended funding, a diagnostic market stimulus, a global public awareness campaign, and reducing antibiotic use in agriculture as key goals toward addressing the issue.
Citing the WHO figure, Fauci said the superbug issue has “the potential for getting out of hand. … You could have as many as 10 million people who will have died in 2050, just 31 years from now—that’s a lot of people.”
In 2015, the Obama administration set forth a five-year plan to combat antibiotic-resistant bacteria, or CARB. Implementation of the wide-ranging executive order “will require the sustained, coordinated, and complementary efforts of individuals and groups around the world, including public- and private-sector partners, healthcare providers, healthcare leaders, veterinarians, agriculture industry leaders, manufacturers, policymakers, and patients … with the goal of saving lives,” the administration said in releasing the effort.
Fauci said that almost five years later the plan has gone well—receiving extensive support and input from multiple federal agencies such as NIH and CDC—and incorporates elements of antibiotic stewardship, surveillance, development of diagnostics, and international collaboration and research.
Thinning the Herd
Michael Bell, a physician and deputy director of CDC’s Division of Healthcare Quality Promotion, said in an interview that superbugs continuing to develop antibiotic resistance are “basically a group of organisms accommodating a stress.” He likened bacteria to an animal herd with thick, hairy coats that, over time, would have trouble surviving a drought or heat wave, while those with lighter, airier coats would be well-suited to reproduce more successfully.
“A couple of seasons or cycles later, you might have a predominance of thin-coated animals,” Bell said. “If you think of the temperature change as the absence or presence of antibiotics, that’s exactly what’s happening.”
Shared biological information is also transmitted among the bacterial populations, as with reproducing animals, he said. “The recipe for resistance can be spread around on what amounts to a genetic thumb drive,” Bell said, making researchers’ jobs more difficult because the next batch of organisms doesn’t have to spend time or energy developing resistance, because it is transmitted genetically. “They use crib notes from the thumb drive, and plug and play,” he said.
The nightmare bacteria report was an attempt to bring material together in one place to give people a sense of what the scope of the issue looks like, and the CDC is planning to release a new superbug report this fall, Bell said.
“Antibiotics generally are a safety net for a lot of medical care,” he said. While modern medics can often save someone who’s been injured in a severe traffic accident, dirt and bacteria that get into a person’s bloodstream will invariably cause an infection. “If we don’t have antibiotics to treat them, the best trauma care is not going to save someone’s life,” he added.
Good Stewardship
Antibiotic stewardship programs, now adopted by most U.S. hospitals, ensure that antibiotics are not overused and are used in the best way possible, said Helen Boucher, a doctor and director of the Tufts Center for Integrated Management of Antimicrobial Resistance in Boston, who has been working on infectious diseases for 20 years. Using antibiotics inappropriately, or overusing them, causes resistance to develop faster, and more resistance in bacteria, which can lead to more infections resistant to antibiotics, she said.
“Antibiotics are a life-saving, incredibly precious resource,” Boucher said. “Before we had antibiotics, soldiers died in wars from skin infections. Ten percent of people who get a skin infection die without antibiotics, but because we have antibiotics, practically no one dies of a skin infection in 2019.
“We want to use the right antibiotic, at the right dose, for the right duration, in every patient,” Boucher said. While many infections have guidelines on which antibiotics work best—part of her work is keeping those guidelines current—“that keeps changing,” she said, in part due to bacteria’s evolving resistance.
Antibiotic Economics
The economics of developing effective and innovative antibiotics are the biggest conundrum in the fight against superbugs, according to everyone interviewed for this story. That’s because key components to prudent antibiotic use include being used sparingly, and the need to continually bring new ones to market—two attributes that don’t translate to profits for shareholders of big, publicly traded pharmaceutical companies when compared with everyday drugs or big-dollar cancer or other specialty pharmaceuticals. This quandary has led to multiple initiatives by groups and public-private partnerships seeking to remedy the situation and to bring new antibiotics into use.
Because antibiotics are treating mutating bacteria, unlike many other drugs they have a limited shelf life, said Matt McCarthy, a New York medical doctor who wrote the book Superbugs: The Race to Stop an Epidemic, published in May (see sidebar). In the book, he writes about how antibiotic development slowed from the postwar “golden age” of the 1950s—after Fleming’s discovery, penicillin production was industrialized in United States the on the eve of World War II—through the early 1990s. Much development since then has been incremental in nature, such as the many derivatives of penicillin, the great-grandfather antibiotic. “But those aren’t going to last as long as if you find a completely new class of antibiotics,” McCarthy said in an interview. “That’s much harder to do.”
One of the largest public-private partnerships is the CARB-X program. Executive Director Kevin Outterson, a professor of health law at Boston University, where the program is based, has worked for more than a dozen years on how law and economics interact with infectious disease, particularly the way antibacterial research and development business models are flawed or can be improved.
CARB-X is investing a half-billion dollars over five years to help projects in early phases of development, in order to help attract more funding. The program is funded by groups including BARDA (the Biomedical Advanced Research and Development Authority, part of the U.S. Department of Health and Human Services), the Wellcome Trust, the U.K. government’s Global Antimicrobial Resistance Innovation Fund, the Bill and Melinda Gates Foundation, the German Federal Ministry of Education and Research, and NIAID.
The program formed in 2016 shortly after the U.S. government’s 2015 plan was put in place. The issue “is both a science problem and a money problem,” Outterson said in an interview, noting a 2016 World Bank report that showed the cost of drug-resistant infections could range from 1.1 percent to 3.8 percent of global GDP—and more in low-income countries—“which puts it in the range of the economic impact of climate change,” he said.
In contrast to potential climate-change costs, which vary locally, “for antibiotic resistant bacteria, there’s a lot of unpriced risk,” Outterson said. “There are a lot of unpriced externalities—people who currently benefit from effective antibiotics, and on the flip side, people who would be harmed by ineffective antibiotics.”
Cancer drugs are an example of a big-dollar pharmaceutical that can cost millions to make and pull in billions once in use, according to Outterson. “There are a lot of billion-dollar cancer drugs. Every one of those drugs presumes the effectiveness of good, antibacterial therapies because many of them severely compromise the human immune system because they’re trying to kill cancer.”
But none of these companies making billions of dollars on cancer drugs are contributing toward antibiotic development, Outterson said. If a patient develops infections from superbug infections such as MRSA (methicillin-resistant Staphylococcus aureus) or E. coli, “it’s not a success if they die from something different,” he said.
After pharmaceutical giant Novartis exited the antibiotic market in July 2018, most of the 140 people working on antibacterial research and development in its San Francisco area labs left to work in other fields, Outterson said. That followed AstraZeneca selling its antibiotics business to Pfizer in 2016, for more than $1 billion.
| Excerpt 1:
Superbugs—From the Ground Level What is a superbug? Some people say it’s a drug-resistant bacteria, while others define it more broadly, said Matt McCarthy, a New York medical doctor, a professor of medicine at Weill Cornell in New York City, and the author of the new book Superbugs: The Race to Stop an Epidemic, published in May. Not all superbugs are bacteria—some are fungi, such as the Candida auris fungus first discovered in Japan 10 years ago that yields high death rates and has shown up in U.S. hospitals, which McCarthy has experience with. Superbugs can be, and are, anywhere and everywhere, though are not always dangerous until and unless they break through to the bloodstream, McCarthy said in an interview with Contingencies. “They are in the poultry section of grocery stores, they’re on doctor’s white coats—they’re really all over the place—but that does not mean that they’re going to cause a disease or an infection,” he said. “People have an immune system that keeps these things at bay, whether it’s your skin as a protective barrier, or the white blood cells inside your body, which can protect people.” While everyone has a risk for getting a superbug infection, the risks are higher for people with compromised immune systems, such as those undergoing chemotherapy cancer treatment, for example. “Most people don’t recognize what their individual risk is, and I think that’s an important thing to recognize and have a conversation with your doctor—are they on a medication or do they have a medical condition that weakens their immune system,” he said. “We really have struggled to communicate the scope of this problem,” McCarthy said. Superbugs includes ground-level views of some of his (anonymized) patients’ struggles with serious infections, and his efforts to bring a new antibiotic, dalbavancin (dubbed “dalba”) to clinical trials, with the attendant regulatory and bureaucratic hoops required to do so. (Spoiler alert: After several false starts, dalba was approved for trials, and he said in June it had been cleared for use, starting later this year.) McCarthy said one of the challenges is that some drug-resistant microbes are pathogenic—cause diseases—and some are not. While worst-case scenarios foresee 10 million deaths per year by 2050, “I don’t take that doomsday approach,” he said. “We have enough antibiotics to treat most infections, but they’re weakening, and microbes are mutating. We’re at this crucial point where we have to invest in new drugs today, so that five and 10 years from now we have treatments available to people. “One of the struggles we have is that hospitals are very uncomfortable talking about superbugs, because they’re afraid patients won’t come to the hospital if they have them,” McCarthy said. “What they don’t realize is that the best hospitals tend to see more superbugs because they have the best diagnostic equipment, the most powerful antibiotics, and the experts who know how to treat them. So we have this war with the [public relations] department about how and when we can talk about the infections we’re treating every day. “It’s a crazy world, the world of superbugs and infectious diseases,” McCarthy said. “We’re still in the muck of it.” —MGM |
“Some of the world’s great assembled research teams scattered to the wind,” Outterson said. “Those people are doing useful things now, but they’re not doing antibacterials. If we lost both [global aircraft makers] Boeing and Airbus, the world would be worried.”
The most recent hit to antibiotic development was earlier this year, when Achaogen—a publicly traded biotech company also based near San Francisco, which had about 100 people working on antibiotic R&D—filed for bankruptcy, just a few months after the U.S. Food and Drug Administration approved its first antibiotic, plazomicin, in July 2018, removing yet another provider in the antibiotic pipeline.
Outterson said plazomicin was valued at a “shockingly low” price at bankruptcy auction. “This drug cost more than $750 million to bring to market, but an Indian generic company bought it for $16 million,” Outterson said. “The price was so low because they’re still going to need to produce, but not sell it, for a number of years. Doctors looked at it and rightly said, ‘Let’s put it on the shelf and try our best to save it for a rainy day,’ but that just isn’t a good business model for a company. You can’t develop a drug where everyone wants to wait 10 years before they use it,” he said.
With big pharmaceutical companies exiting antibiotic development, CARB-X has focused on co-funding projects by smaller biotech firms around the world, many of which have as few as 10 to 15 employees. Such projects need a boost because while a cancer drug breakthrough could mean billions of dollars, without help the same group of people working in antibiotics could end up in or near bankruptcy, Outterson said.
‘SPARKing’ the Data
The Pew Charitable Trusts has also been active in helping to address the antibiotic issue. It’s spearheaded development of a shared research platform called SPARK—Shared Platform for Antibiotic Research and Knowledge—an interactive tool to help academic and company researchers around the world collaborate and share knowledge of new antibiotic development to target Gram-negative bacteria.
The publicly available tool allows researchers to access data from published studies and previously unpublished data, and to create models and test hypotheses to generate new insights into treating the toughest bacteria, said Allan Coukell, Pew’s senior director of health programs. Novartis and Achaogen have contributed research to SPARK so far, and Pew expects more to join in the future.
“Right now, there are very few companies developing new antibiotics,” Coukell said. “If we don’t develop more, it will only be a matter of time before untreatable bacteria become more common.”
Good stewardship—including slowing/reducing overuse of antibiotics in human and agriculture use—and the development of new antibiotics are two things that need to be done simultaneously. “Right now, the market is not developing enough antibiotics—in particular, enough innovative ones—to meet our current needs, much less our needs in the future,” Coukell said.
Could superbugs wreak havoc along the lines of an infectious disease horror movie? “They absolutely could,” Coukell said. The official CDC number of 23,000 U.S. deaths per year due to superbugs “is like a jet airliner crashing every week—and that’s likely an underestimate,” he said. “While the vast majority of infections can still be treated with existing antibiotics, you never know when some bacteria are going to mutate and spread, whether it’s from somewhere else in the world or here in one of our own hospitals, and you could suddenly have a bacteria that’s resistant to everything we’ve got.”
While it likely wouldn’t be a highly contagious situation such as Ebola, Coukell noted that about 20 years ago the superbug carbapenem-resistant Enterobacteriaceae (CRE), which was resistant to all but one drug, showed up in a few states before spreading quickly throughout the country.
“We’ve already got lots of infections that you can only treat with one drug, so if all of the sudden that becomes ineffective, you could have a real pandemic on your hands and it would take a long time to get control of that,” he said. Going to the dentist, getting surgery after a car accident, or being treated for cancer would become much riskier—“all that gets back to a pre-antibiotic era when a lot of people died from simple infections. It’s a train wreck, but it’s a slow-motion train wreck,” Coukell said.
| Excerpt 2:
Reinsurance Ramifications Like any big global issue with the possibility of putting a major dent in the world’s collective health—and GDP—the issue of a potential superbug contagion raises the possibility of reinsurance coverage. Large-scale public health networks straining at an outbreak of any disease could trip economic dominoes worldwide. A report released last November by the Paris-based Organisation for Economic Cooperation and Development, Stemming the Superbug Tide: Just a Few Dollars More, states that superbug infections could kill 30,000 Americans per year by 2050, and about 2.4 million people in North America, Europe and Australia over the next 30 years unless more is done to stem antimicrobial resistance (AMR). Three out of four deaths could be averted by spending about $2 per person per year on basic things like handwashing and more prudent antibiotic use, the report notes, and dealing with AMR complications could cost on average up to $3.5 billion a year across the 33 countries included in the report’s analysis, unless countries step up their fight against superbugs. “There have been discussions that this is something for which there should be a reinsurance market,” said Kevin Outterson, executive director of Boston University-based CARB-X, a nonprofit public-private partnership that pulls in global funding and resources to stimulate development of new antibiotics to combat superbugs (see main story). “The systemic global risk that no one is really pressing, nobody is insuring … I would love to provoke a discussion—or a meeting or workshop—in which the reinsurance industry reacted to this, because they might find a way to make a market that would price and pay for some of this risk in more appropriate ways than what we’re doing now,” Outterson said. Two global reinsurance firms that agreed to be interviewed on the subject said they were indeed paying attention to the superbugs issue. “A significant AMR event would have a significant impact on reinsurance portfolio performance,” said Andreas Tacke, chief medical consultant at Hannover, Germany-based Hannover Re, the fourth-largest reinsurance company in the world. “In the future, when looking at human medicine, AMR might have a greater impact on children, the elderly, or people with a weaker constitution, as well as all populations with a high burden of disease, reflecting the insurance markets that are most likely to see the effects of the prevalence of superbugs.” Among the many high-level global studies, Tacke cited a 2016 report commissioned by the U.K. government that about 700,000 global deaths could be attributed to AMR every year and, if that threat goes unabated, could climb to near 10 million by 2050 and become a major topic for the reinsurance industry. “This is a concern for public and private health care and insurance systems,” Tacke said. “Depending on the scope of an outbreak, it might also effect governments and public institutions.” He said pandemic risks are taken into account when it comes to price calculation, which influences different business segments. For underwriting, the best- and worst-case scenarios are calculated for the event of a superbug or pandemic outbreak, and possible threats could be covered in traditional reinsurance solutions. “There are a variety of scenarios created by superbugs,” Tacke said. “These developments may create substantial claims for the reinsurance industry. Areas at risk are contingent business interruptions, medical malpractice, veterinary medicine, and life and health policies.” Zurich-based Swiss Re, the world’s second-largest reinsurance firm, has a pandemic model that includes an AMR parameter, according to Christoph Nabholz, the company’s head of life & behavior research and development, and Urs Widmer, senior life guide medical officer, who provided answers for an interview for this story. A percentage of influenza deaths can be caused by lung bacterial superinfections, and a high degree of AMR would increase the mortality impact of an influenza pandemic, they said. Superbugs like methicillin-resistant Staphylococcus aureus (MRSA) can be treated in outpatient settings, but most superbug outbreaks are in hospitals or in intensive care units, where proximity and immune-compromised hosts and in-dwelling devices such as catheters aid the spread, the two said, while large-scale hospitalizations caused by AMR bacteria outside the hospital setting are less likely. Public health concerns tend to focus on the developing world, because superbugs are potentially more prevalent there due to lack of effective antibiotic stewardship and high levels of antibiotics used as growth factors in animal and fish production, Nabholz and Widmer said. No big superbug outbreaks have been reported in developing countries, but they may be underdiagnosed, and superbugs from developing countries transported to Western countries by medical or regular tourists could cause superbug outbreaks in hospitals, which would be costly, they said. —MGM |
DISARM Legislation
Superbugs and antibiotic development have also caught the attention of federal lawmakers. Bipartisan legislation introduced in the U.S. Senate would offer so-called pull incentives to spur antibiotic development. In June, Sens. Bob Casey (D-Pa.) and Johnny Isakson (R-Ga.) introduced the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act of 2019 to help advance research and new treatments for drug-resistant infections.
The bill would give financial incentives to companies after antibiotics have been brought to market, said Amanda Jezek, senior vice president for public policy and government relations at the Infectious Diseases Society of America, which supports the legislation.
DISARM “promotes appropriate use of antibiotics,” Jezek said. It includes provisions to change the way Medicare reimburses hospitals for new antibiotics, by carving new antibiotics out of the diagnosis-related group (DRG), a patient classification system that standardizes prospective payments to hospitals and encourages cost-containment initiatives. It would also require hospitals—in order to get their entire payment for antibiotics—to implement antibiotic stewardship programs in line with CDC recommendations, and require hospitals to report their antibiotic use and resistance data to CDC.
“It’s not a silver bullet, but it could help stabilize the market. Appropriate use of antibiotics is unlikely ever going to provide high enough levels of predictable [return on investment] for sustainable investment,” Jezek said. “Bacteria don’t care if you’re a Democrat or a Republican. There’s a pretty good understanding on both sides of the aisle that antibiotics are unique, and that there’s a unique market failure here, and a need to do something specific and targeted to separate antibiotics from the larger drug-pricing effort.”
While pull incentives would give companies tools such as longer period of market exclusivity once their antibiotics are approved, McCarthy, the Superbugs author, took it a step further and said that in addition to pull incentives, drug companies should also get “push” incentives—things such as tax breaks to entice drugmakers to develop new antibiotics.
“This is where I disagree with a lot of experts,” he said. “I think we need to take drastic, not subtle, measures. If we stay at the current funding model and the current market support for drugs, there will not be sufficient antibiotics to treat most run-of-the-mill infections. It might not be popular to give big pharmaceutical companies a tax break, but I think that’s what we need to do in order to get them to put up a billion dollars to try to develop a new drug.”
Experimental Treatments
One researcher has worked for the past 30 years identifying bacteriophages—viruses that can kill bacteria. Phages were discovered about 100 years ago, said Graham Hatfull, a professor at the University of Pittsburgh’s Department of Biological Sciences.
“The interest in using phages therapeutically now is at one of its high points, in large part because of the concern about superbugs,” said Hatfull, whose lab has about 15,000 phages stored in its freezers, contributed over the past decade from more than 130 U.S. college and university undergraduate researchers. To narrow the search for effective matches to treat superbugs, the lab uses genomic information and tests bacteriophage subsets on particular types of bacteria.
“Bacteriophages are the majority of biological life in the world,” Hatfull said, offering an estimate of global naturally occurring bacteriophage particles of 10 to the power of 31, which tops the number of all combined animal life forms on the planet. “They’re small, but there’s lots of them. They’re viruses, so they spend their time infecting bacteria and making more of themselves.”
The goal is to match a bacteriophage with the strain of a patient’s superbug infection, which can “stack the deck and lead to a good clinical outcome of saving a patient’s life,” he said. “It’s a complicated topic of how and where you might want to use these interventions. I’m hopeful that in the next few years we’ll be able to figure out circumstances—diseases and bacteria for which it will be useful, and others for which it won’t.”
Last year, the lab was able to find a mix of bacteriophages in its vault helped to heal a teenage girl in London with cystic fibrosis who was suffering from a virulent infection after a double-lung transplant. The lab used three bacteriophages: “Muddy,” which originated in South Africa; “Zoe J,” from a researcher at Providence College; and “BPs,” isolated by a University of Pittsburgh student.
The girl had acquired a severe bacterial infection following her transplant, in part due to immunosuppressant drugs, and was facing a dire palliative care situation. After her mother scoured the internet for options, doctors in London sent a strain of the infection to Hatfull’s lab, and his team went to work, searching for about six months until they began treatment in June 2018.
Six weeks later, the girl’s liver infection was essentially gone, her breathing improved, and the skin nodules caused by the infection diminished greatly. While the girl still has CF, she has gone back to school and “has basically returned to what is in effect a pretty normal life. She’s doing remarkably well,” Hatfull said.
Michael G. Malloy is managing editor for member content at the Academy.
References
[1] Vital Signs; CDC; April 2018.
[2] No Time to Wait: Securing the Future From Drug-Resistant Infections; Report to the Secretary-General of the United Nations; April 2019.
[3] Tackling Drug-Resistant Infections Globally: Final Report and Recommendations; The Review on Antimicrobial Resistance; May 2016.
[4] Drug-Resistant Infections: A Threat to Our Economic Future; World Bank; March 2017.
[5] Stemming the Superbug Tide: Just A Few Dollars More; OECD Health Policy Studies; OECD Publishing, Paris, 2018.
[6] Tackling Drug-Resistant Infections Globally: Final Report and Recommendations; The Review on Antimicrobial Resistance; May 2016.
