Antimicrobial Resistance: The Silent Pandemic

We are on the precipice of a looming crisis. Antimicrobial resistance (AMR) is the evolution of deadly pathogens like bacteria and fungi to resist all current antimicrobial medicines. In this episode, we talk about how the dwindling supply of new antibiotics is fueling this silent pandemic, and why we need a continued pipeline of new antibiotics to avoid this crisis. Guests: Ankit Mahadevia, Spero Therapeutics; Henry Skinner, AMR Action Fund; and Mary Dwight, Cystic Fibrosis Foundation

Speaker 1 (00:02):

Penicillin was distributed in 1943, and widespread penicillin resistance arrived by 1945. Vancomycin arrived in 1972, vancomycin resistance in 1988. Daptomycin, one of the most recent drugs, in 2003, and resistance to it just a year later in 2004.

Speaker 2 (00:22):

In just a few days, some of the E. Coli bacteria figure out how to resist the Cipro and survive in what should be a deadly environment.

Speaker 3 (00:33):

Doctors around the world are struggling to cure some secondary illnesses that have popped up that people are contracting while they are treating the coronavirus, and those illnesses may be contributing to an already growing antibiotic-resistant pandemic.

Dr. Michelle McMurry-Heath (00:52):

As we approach two years of the most dangerous and widespread pandemic in a hundred years, concern about whether we are prepared for the next one is growing, but we are already on the precipice of a looming crisis, the one of antimicrobial resistance. Antimicrobial resistance, or AMR, describes the evolution of deadly pathogens like bacteria and fungi to resist all current antimicrobial medicines. Today, we'll talk about how our dwindling supply of new antibiotics is fueling this silent pandemic, and why we need a continued pipeline of new antibiotics to avoid this crisis. I'm Dr. Michelle McMurry-Heath, and you are listening to I am BIO.

Mary Dwight (01:38):

A 19-year-old woman with cystic fibrosis from New Jersey, she's cultured MRSA since she can remember. Only two antibiotics have made a difference for her when she's been sick. As a child, she routinely took these antibiotics, which were usually enough to rebound her back to her baseline lung function before the immediate infection that she'd been treating. So they were working for her, but she was using those two chronically. She was using them routinely, and with that routine use came waning effectiveness. When she turned 16, those two antibiotics weren't making the cut anymore, and she got sicker, leading to an elongated hospital stay that caused her to miss significant amounts of school and really jeopardized her health.

Dr. Michelle McMurry-Heath (02:41):

This is Mary Dwight, Senior Vice President of Policy and Advocacy at The Cystic Fibrosis Foundation. The story Mary shared is an all too common tale of the silent pandemic of antimicrobial resistance.

Mary Dwight (02:55):

So that's a great example unfortunately, of first of all, winnowing antibiotic options for someone period at the outset of an infection, and then the impact of using those same two antibiotics over and over, ultimately again, winnowing their effectiveness and leaving her with very few, if any, options.

Dr. Michelle McMurry-Heath (03:17):

If current trends continue, existing antibiotics could stop working all together in the near future, leaving humanity vulnerable to deadly drug-resistant superbugs. To outrun these superbugs, we need to continually develop new and more potent antibiotics.

Henry Skinner (03:36):

Antimicrobial resistance is the gained ability of a bacteria, or fungal pathogen, or virus to evade the power of a therapeutic, of an antibiotic to kill that pathogen, and to treat and cure an infection. There are many mechanisms by which pathogens develop capability to avoid an antibiotic, and pathogens can have multiple resistance capabilities, thereby becoming multi-drug resistant, and in some cases becoming resistant to every antibiotic that we have developed to date from the 1930s until today.

Dr. Michelle McMurry-Heath (04:16):

This is Henry Skinner.

Henry Skinner (04:17):

My name is Henry Skinner. I'm the Chief Executive Officer of the AMR Action Fund. The AMR Action Fund is the largest venture fund focused specifically on investing in new drugs to treat AMR or drug-resistant infections caused by bacteria and fungi. We invest in private innovative biotechnology companies that are researching and developing the next generation of antibiotics designed to treat significant human infections caused by pathogens, and specifically those that have identified by the CDC and the WHO as global priorities. Bacteria, fungi, and viruses will always develop ways around our therapies, so these miracle drugs that were developed over the last almost hundred years now are beginning to fail us as resistance has come to be. It's interesting also bacteria can share their resistance, and so once you get resistance in one bacteria, they can pass that on to other bacteria, thereby accelerating drug resistance and compounding the problem for us. The only question is how quickly we can identify the resistance, and we can limit that spread through appropriate stewardship.

Dr. Michelle McMurry-Heath (05:38):

Henry explained why we find ourselves in a world threatened by superbugs becoming resistant to available medicines. It's quite layered.

Henry Skinner (05:47):

So the overuse of antibiotics is the treatment of a patient... There's two parts. One, you treat a patient who perhaps comes in with a cold, and you give them an antibiotic because bacteria could be caused by a common cold virus. If you're treating someone with an antibiotic for a infection caused by a virus, this won't do any good, and it only can do harm by facilitating the development of resistance because you're not treating the right infection.

Henry Skinner (06:18):

The underuse is that you are not treating the infection fully. So you begin to treat someone and maybe you need to take the antibiotic for two weeks to eliminate the infection. You take it for four or five days. You feel a lot better. You forget to take it going forward, but the bacteria is still there. Maybe you're not as sick as you were, but because you haven't eliminated it, you've created an opportunity for it to develop resistance as well. Then thirdly, underuse would be using too little of an antibiotic. So just enough to maybe slow down the bacteria and give it a chance to develop resistance, rather than killing it off. This can happen from a number of reasons. Bacteria become partially resistant, so you have to have a higher concentration of antibiotic, and if you don't have enough concentration, you're essentially encouraging the bacteria to become stronger and to be able to evade that antibiotic. So all of those things conspire.

Dr. Michelle McMurry-Heath (07:19):

Henry explained the magnitude of the problem.

Henry Skinner (07:23):

AMR is a global health threat, and let me give you some facts to provide some evidence here. So antibiotic-resistant infections kill, this data goes back a few years, but 30 to 50,000 people in the US every year, about the same number Europe, over 700,000 globally, so already we're in, I would say a fairly substantial crisis if we think about the mortality and the morbidity caused by the infections. It's been estimated that more than 10 million people will die from antibiotic-resistant infections in 2050. So just less than 30 years out, we're talking 10 million a year, which puts us kind of on the scale of where we are with COVID, and costs societies trillions of dollars, both in direct costs and in indirect costs, and limit the ability of a number of countries to develop as they could otherwise.

Dr. Michelle McMurry-Heath (08:21):

We are all vulnerable to the AMR threat, but people with compromised immune systems are especially so. Cystic fibrosis patients are one such at-risk group. Mary tells us more about the resistant microbes impacting that population.

Mary Dwight (08:39):

Cystic fibrosis is a life-threatening genetic disease that makes the body produce thick, sticky mucus that clogs the lungs and other organs, and leads to respiratory infections and other challenges. It's a rare disease that affects about 30,000 children and adults in the United States, and there is no cure for cystic fibrosis. As people with CF are living longer, their disease is manifesting in different ways, and they're confronting new challenges related to life with cystic fibrosis, including difficult-to-treat infections for which no effective antibiotics are available.

Mary Dwight (09:17):

It's certainly at the top of our agenda to help people with CF live free from illness, including these antibiotic-resistant infections. Those infections, or chronic respiratory and lung infections, are really a hallmark of life with CF because of that persistent mucus in the lungs of people with the disease. People with CF are also prone to infections because their mucus and airway liquid does not have the same infection-fighting properties as normal mucus. Because of these heightened vulnerabilities and infections, the routine use of antibiotics in CF care is medically necessary and quite common. However, people with CF find themselves battling difficult-to-treat infections for which no existing antibiotics are effective.

Dr. Michelle McMurry-Heath (10:08):

As Mary explains, the experience of cystic fibrosis patients provides a stark warning to the rest of us.

Mary Dwight (10:15):

So we see cystic fibrosis as a microcosm for the risk of persistent antibiotic use and the potential effects of antibiotic-resistant organisms. Despite significant progress in treating CF, infections remain a serious problem that may lead to decrease in a person's lung function, increased and elongated hospitalizations, worsening lung disease that may require lung transplant, and unfortunately, even death. If I could, let me share the story of just one man who was living with CF with a drug-resistant pseudomonas. He lives in Kentucky and his pseudomonas is resistant to every known antibiotic approved to treat the infection. In 2017, he was really out of options, and he was put on a new IV medication that ultimately shut down his body, accumulating with potential liver damage. He continues using this very intense antibiotic today, despite the damage it's doing to his body, because without it, he wouldn't be able to address the pseudomonas, which is ultimately a bigger risk once it colonizes his airways, and is incredibly difficult to eradicate. So you can see his story is really the microcosm of the challenge we're facing with antibiotics.

Dr. Michelle McMurry-Heath (11:35):

With that burden of antimicrobial resistance looming, why not just make stronger drugs? We answer that question when we return from a short break. Are you signed up for Good Day BIO? It's the daily five minute newsletter at the intersection of biotech, politics, and policy. Become a subscriber today at bio.org/goodday. This silent pandemic of antimicrobial resistance is both widespread and obscure, but in every corner of our medical system, there are stories like these.

Mary Dwight (12:23):

Again, I'd love to share the personal story of someone who is battling this disease. A young woman in California in this case, dealing with a persistent case of B. cepacia that at its worst led to frequent hospitalizations and exacerbations [inaudible 00:12:38] her lungs that required treatments for every three to four hours just to breathe. In 2018, when she was dealing with one of these infections, she caught another virus leading to a 12 day hospitalization, and in 2019, it was recommended she receive a double lung transplant because of the deterioration of her lungs, the swiftness of which was a direct cause of that B. cepacia infection. So we see that this rare disease, cystic fibrosis, really is a harbinger of some of the challenges for antimicrobial resistance. So we really know that these challenges that the CF population today are challenges that a larger population may face tomorrow if we don't continue to manage antimicrobial resistance and develop these new antibiotics.

Ankit Mahadevia (13:33):

Now, we've all learned our pandemic over the last two years was caused by a pathogen that was obscured to most of us in 2019, but then changed our world for the worse over the last two years. We've all seen, we've read the news, we might have even taken care of patients, just how frustrating it was when once we knew the need, we had to play catch-up to be able to find therapies and vaccines that would work. We need a framework so that we can make that make sustainable sense for our company.

Dr. Michelle McMurry-Heath (14:03):

This is Ankit Mahadevia.

Ankit Mahadevia (14:05):

My name is Ankit Mahadevia. I'm co-founder and CEO of Spero Therapeutics. A group of us founded Spero using a blank sheet of paper, and our vision was that we wanted to focus all of our energies on finding solutions to the biggest problems patients face due to infection. We at Spero are clinicians, we're pharmacists, we're nurses, we're biotech executives, and we want to make patients better and see positive change overall in all of the systems we have to address antimicrobial resistance. So what we do to do our part for that solution is we discover, we develop, and we aim to bring to market novel therapies that solve problems that the other medicines we currently have can't.

Dr. Michelle McMurry-Heath (14:56):

As Ankit describes, the market isn't quite designed to incentivize the creation of stronger drugs against antimicrobial resistance.

Ankit Mahadevia (15:06):

Our healthcare system, and especially true in the US, but also worldwide, we provide payment for the number of times we use a given medicine or a procedure, and there's two buckets of patients that need help with infections. The first bucket is kind of like the opportunities that we've tried to build our company around where it's still a focus group of patients, but there's still enough patients where we think that when we deliver the medicine to who should get them, that we can sustain and build a company and continue investing in future antimicrobial therapies. Now there's a second bucket of unmet needs for patients where the microbes themselves that are causing patients harm are frightening, but there may just not be enough of them today here in 2021 to create an economic case that our drug development companies can use to spend the hundreds of millions of dollars it requires to develop these medicines.

Dr. Michelle McMurry-Heath (16:07):

Henry Skinner from the AMR Action Fund also addresses the broken market when it comes to developing new antibiotics.

Henry Skinner (16:16):

Antimicrobial drugs aren't available now for a couple of reasons. The most important one is that the market for antimicrobials, for antibiotics is a very unique market, and unlike any other pharmaceutical market. In every other market... If you develop a drug to treat migraine, you want to maximize the availability of that drug to everyone with a migraine. You want to treat everyone with it. The market for antibiotics is different. You only want to treat a patient who has the right sort of infection for that particular antibiotic. So you want to limit its use only to where it's absolutely necessary. The value that these products bring is not tied to the volume of use. It's really tied to the benefit to the patient it's given to who otherwise would have no hope, and perhaps die from that infection.

Henry Skinner (17:17):

So if your product is highly valuable for those patients, will be even more valuable in the future as resistance grows, but you're not selling a whole lot of that product today. You just can't afford to... You don't earn a return on your investment in order to finance the next round of innovation. So all these things conspire, the market grows slowly, and we as society want to limit the use of these drugs only where they need to be used, which in today's marketplace where you're rewarded for the volume, not the value of what your drug provides, we have a inverse relationship and a failure of the commercial market. Fundamentally, what we need to do is we need to reward the innovators for the value they bring to the system, and the value they bring to the system measured in a way that's different than we've done it in the past.

Dr. Michelle McMurry-Heath (18:24):

Ankit adds more.

Ankit Mahadevia (18:26):

The reason commercialization of medicines today against those threats is uncertain is because we have a healthcare system that provides a return for the number of times you use a medicine, and in the case of infection, it's not always true that the most important medicines you develop are the ones you're going to use the most often today. We want to prevent the next pandemic from being one where we're playing catch-up because we didn't have the incentive to develop medicines that could help us.

Dr. Michelle McMurry-Heath (18:54):

Without the right incentives and a workable marketplace, even if a company has a brilliant FDA-approved solution to a resistant microbe, there's no guarantee that the company will remain viable.

Henry Skinner (19:08):

We've had a number of bankruptcies of companies that have developed successful antibiotics. Company called Achaogen, another one Melinta, who had four approved antibiotics. Both of these companies went bankrupt because these new antibiotics were not selling sufficiently to cover their costs.

Dr. Michelle McMurry-Heath (19:26):

We need a solution. We're facing a ticking time bomb that could kill up to 10 million people annually by the year 2050.

Ankit Mahadevia (19:36):

The great news is, as we look at this vexing problem of antimicrobial resistance, that a lot of really thoughtful minds have worked very hard to create frameworks that can help future patients that suffer from infectious threats that are going to come. One example is something called the PASTEUR Act.

Dr. Michelle McMurry-Heath (19:57):

The PASTEUR Act stands for Pioneering Antimicrobial Subscriptions To End The Upsurging Resistance Act. The proposal creates a subscription-style program. The federal government would have access to new antibiotics in exchange for fixed recurring payments. Ankit explained why he supports this framework.

Ankit Mahadevia (20:20):

I think that's important because it allows us to get the most out of the talented men and women and the infrastructure we have to develop medicines for infection, and I think a framework like PASTEUR can bring the right minds to the table so we're using all of our energies for all of the threats that face society, and not just the ones that our current system can sustain.

Dr. Michelle McMurry-Heath (20:41):

The PASTEUR Act was introduced this summer, but has yet to be passed. However, it was included in a health policy package that was recently introduced in the House, Cures 2.0, which indicates positive movement on this critical policy. The PASTEUR Act is not the only solution that could help. There's also the DISARM Act. DISARM stands for Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms Act. This proposal would adequately reimburse hospitals that responsibly prescribe novel antibiotics, thereby incentivizing firms to create them. This act was introduced in the House earlier this year and is also awaiting action.

Ankit Mahadevia (21:29):

So what we need, and I urge all of your listeners to call their lawmakers and support frameworks that already exist that try to address the disconnect between the fact that pathogens that could threaten our society aren't here yet, but they will be, and we need to develop solutions ahead of the game, rather than playing catch-up.

Dr. Michelle McMurry-Heath (21:50):

In the meantime, companies like Spero are still putting their all into developing new antimicrobial medicines.

Ankit Mahadevia (21:57):

I was inspired to develop antibiotics just through my training. I'm a clinician by training, and based on that, I've had a front-row seat to see how antibiotics can be transformative. Actually, my first patient in medical school had urosepsis, or urinary tract infection that spread to his blood. Just early in my training, watching that as you found the right antibiotic, you go from being very concerned for your patient to watching him have breakfast with his kids after the course had cleared the infection. Just really gives you an idea of how transformative these medicines can be. I think that there's very few interventions in medicine that can be as profound and have as big an impact as quickly. Unfortunately, there is just a lot more that we can and have to do to make sure that these medicines are available for us, and for our kids, and for our grandkids. I'm inspired along with my teammates at Spero, that we can be part of the solution. As our medicines succeed, we can touch every part of patient care just given how widespread the need for good antibiotics is all over healthcare.

Dr. Michelle McMurry-Heath (23:03):

And of course the AMR Action Fund is also doing incredible work to support at such companies.

Henry Skinner (23:11):

Yes, well I think this is probably a problem that's bigger than the AMR Action Fund, but what the AMR Action Fund is doing to help address the broken market for antimicrobials is first and foremost, we have a billion dollars that we're going to invest in clinical development to make sure that we continue to have a pipeline of new antibiotics to treat these drug-resistant pathogens that are providing so much risk to our future. By doing that, we are, if you will, buying time for our policymakers to better understand the challenge of this marketplace and what we need to do as a society to create a sustainable ecosystem to finance innovation, so that we always have new antibiotics when we need them. In addition, we are trying to highlight the challenges that innovators face, and financiers face in bringing forward the needed next generation of antibiotics.

Henry Skinner (24:13):

So we're trying to educate and help policymakers understand the challenges that we face, the costs, the difficulties in progressing these things, not only from a scientific standpoint, but from a future market standpoint, than if we don't get these essential changes to the marketplace and fix the market, we will not continue to have new antibiotics at the ready when we need them. We've been blessed with COVID to see vaccines developed in less than 12 months from the identification of COVID-19. It's just been absolutely remarkable what that public-private partnership has done to bring the vaccines to patients so that we can get out of the pandemic. Drug discovery for new antibacterials is a much different timeline. It takes on average 10 to 12 years to develop a new antibacterial. We have to stay ahead of it. We have to advance in our future, and we have to maintain this investment in what's fundamentally the foundational or infrastructure of our healthcare system.

Dr. Michelle McMurry-Heath (25:24):

We're so grateful to the AMR Action Fund for the work they do. Thank you to all of today's guests, Henry, Ankit, and Mary. Make sure to subscribe, rate and/or review this podcast and follow us on Twitter, Facebook, and LinkedIn at I Am Biotech, and subscribe to Good Day BIO at bio.org/goodday.

This episode was developed by executive producer Theresa Brady, and producers Connor McKoy, Cornelia Poku, and Marilyn Sawyer. Sound design and mixing by Jess Fenton. Theme music created by Luke Smith and Sam Brady.

Sadly, this is the last episode of the season. We'll miss putting out our new episodes, but please check out our archives for anything you may have missed. During the break, the producers and I are going to enjoy the holidays with our families, even as we continue supporting the amazing research and innovations that we've highlighted all season long. I'm also going to take some time to finish writing my book, but you'll hear more about that in the new year. So thanks for listening. We'll be back in March with more incredible stories of biotech breakthroughs. See you in the spring.