This transcript has been edited for clarity.
Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape. I'm delighted to have a conversation with Dr Matt McCarthy of Weill Cornell faculty. He's the author of three books and his new book is called Superbugs: The Race to Stop an Epidemic. Matt, welcome.
Matt McCarthy, MD: Thank you for having me.
On Writing and Medicine
Topol: You have been writing for a while and you are young, so how did you get started in this career sideline?
McCarthy: I kind of fell into it. A lot of my friends happened to be writers. I was an undergraduate at Yale, and after college my closest friends became a novelist, a screenwriter, and a writer for Sports Illustrated. I was a baseball player and had some baseball stories to tell, and that led through a somewhat meandering process to my first book, which was about Minor League Baseball. After that chapter of my life ended, I went into medicine and I wrote about my first year as a doctor—the ups and downs of my intern year. Most recently I wanted to broaden my writing experience, and rather than doing another memoir, I wanted to write about an issue that I was seeing every day in the hospital, which is the rise of antibiotic-resistant microbes.
Topol: Just so everyone knows about your past accomplishments, your baseball book was called Odd Man Out: A Year on the Mound with a Minor League Misfit. You were on the baseball team at Yale, right?
McCarthy: That's right. It has been fun to see the trajectory of my Yale baseball teammates. One is now the governor of Florida, one is the general manager of the Baltimore Orioles, and another one got two World Series rings with the Boston Red Sox.
Topol: That is amazing. Your second book was The Real Doctor Will See You Shortly: A Physician's First Year. That was about your medical training?
McCarthy: Yes. I went to Harvard for medical school, and when I graduated I was full of confidence and optimism. I became an intern at NewYork-Presbyterian Hospital up at Columbia on 168th Street. During one of my first nights on call in the cardiac care unit, I misdiagnosed someone and the person almost died because of an error that I had made. All of the confidence and enthusiasm that I had evaporated in an instant. The book looks at, how do you recover from that? There was a lot of talk about how to prepare and cope for intern year, but that specific moment was something that I had never really encountered before. I tried to recover from that in ways that I thought would be interesting to write about. I also became very close with a patient who was living in the hospital waiting for a heart transplant. I would see him every day riding on a stationary bike. I thought that his journey in some ways was somewhat similar to mine because we were both just showing up at the hospital every day, trying to make it through. But, of course, there are limitations to that comparison. That first year was a formative time for me and one that I was really excited to write about.
Topol: You then went on to get infectious disease specialization and that is what you do now.
McCarthy: That's right. I do a mix of general medicine and infectious disease. My clinical and research expertise is in fungal infections. The joke in my house is that my wife, who is a transplant nephrologist, likes to say that of all the guys she could have met, how did she end up with the yeast infection guy? But that is really what interests me and it's taken on a renewed importance now that we have this multidrug-resistant yeast infection spreading around the globe, Candida auris. That is one of the areas I focus on a lot.
Topol: That is a good transition to your new book. You have a really good sense of humor, which comes through in Superbugs, and I'm sure it does in the other books as well. That helps when you are transmitting a lot of information and telling stories. You mentioned C auris, but the other major substrate in the book relates to methicillin-resistant Staphylococcus aureus (MRSA) and other multiresistant organisms. Could you set the landscape and first define the term "superbug"?
What Is a Superbug?
McCarthy: The definition is actually quite controversial. Many people refer to it as simply drug-resistant bacteria. I take a somewhat broader view, which is to say that it also encompasses drug-resistant fungi, parasites, and protozoa, and some people would even say viruses. One controversial question is: Is influenza a superbug? If you take that broader view, the scope of the problem is really concerning. In fact, the World Health Organization just came out and said that by 2050 we could expect 10 million deaths worldwide every single year from superbugs if we don't confront this problem.[1]
This was something that doctors were talking about and researchers were thinking about, but I don't think the lay public appreciated the full scope of this issue, and that was what really led me to get into this. After the book came out I received an email from a professor who said, "I don't like the term 'superbugs' because I prefer the term 'difficult-to-treat infections.'" I said, "Well, that's not really a great book title. Also, not all of them are difficult to treat. I saw a patient 2 days ago who had a multidrug-resistant urinary tract infection, but the infection was susceptible to an oral antibiotic and I treated the guy in the emergency room (ER) and sent him on his way." Just sort of explaining what a superbug is turns out to be a relatively complicated endeavor.
Topol: You certainly have come up with a good way to frame that. The book is in two parts: You bring us back to the history of antibiotics and how we got to the point where we are today, and then you take us through a clinical trial you worked on which had all sorts of hills and valleys. Tell us more about this complicated trial.
Dalbavancin Trial
McCarthy: The reason I took on this trial was that I discovered something rather surprising when I became a staff physician, which is that many of the newest antibiotics that are approved by the US Food and Drug Administration (FDA) aren't necessarily added to hospital formularies. If you walk into your local hospital, it probably isn't carrying the drugs that were approved last year or even the year before. That is because they are tremendously expensive. An antibiotic typically costs about a billion dollars to develop and can take about 10 years of preclinical and clinical testing before it's approved. Companies charge a very, very high fee for these drugs to make back their investment. I took on a trial with an antibiotic called dalbavancin, which costs thousands of dollars for a single dose that our hospital had refused to carry.
I convinced Allergan to give me some of the drug for free and to run a trial and find out whether we could use this drug in a way that benefits patients, the hospital, the providers, and that also makes pharmacoeconomic sense. I thought this clinical trial was a nice lens to look through at the problem of superbugs and antibiotics. I went up to patients and said, "I've got a new drug. Would you like to try it?" And they said, "Have you ever given it to anyone before?" And I would say, "No." They would say, "Has anyone at this hospital ever given it to anyone before?" And I'd say, "No." They would say, "Well, why me?" That was a very powerful doctor-patient interaction that I wanted to explore in writing.
Mentorship
Topol: You certainly took us through that and all of the different challenges that you confronted. You worked closely with your mentor, Tom Walsh. Can you tell us more about that relationship?
McCarthy: When I was a resident, I interviewed for fellowship programs. And when I came to Weill Cornell, I met a guy named Tom Walsh. He was moving his office from the National Institutes of Health (NIH) to Cornell and we just bumped into each other in the hallway. It was one of these moments where you just meet someone and you say, "I'm going to work with that guy," and he and I have been sort of attached at the hip for the past 10 years. He has a very unique background in that he is trained in both adult medicine and pediatrics and he is trained in oncology and infectious diseases. He is also a world-class mycologist and has what seems like a photographic memory. I went under his tutelage and I chose to write about him because I think mentorship is important.
Also, because superbugs are so rare in some cases, there are no data to drive doctors in decision-making. They have to make frantic phone calls to experts like Tom Walsh, and I don't think that people always appreciate that. This was the man who was getting calls in the middle of the night from Berlin and Sydney and all over the place, from people asking, "I've got a kid who has a multidrug-resistant infection; what do we do?" This was the man who was making pharmacokinetic calculations in his head and making life-and-death decisions about patients he'd never met. I thought that was something that needs to be talked about and also captures what is so exciting about infectious diseases.
Patient Encounters During the Dalbavancin Trial
Topol: It's really extraordinary. Along the way with testing of the antibiotic dalbavancin, you got into some really interesting patient encounters. Could you tell us about a couple of patients?
I just have one question for you: Would you give this drug to your own mother?
McCarthy: The first person who I ended up giving the drug to was a lawyer, and he was somebody very familiar with reading consent forms and with reading the nuances of a legal document that I was handing him to sign away. I talked with him about the risks and benefits of the trial and handed him the long consent form. What I thought was so interesting was that he put it down, looked me in the eye, and said, "I just have one question for you: Would you give this drug to your own mother?" It kind of caught me off-guard. That is such a great question for a clinical investigator who is bringing in a new drug. I fumbled for a moment and eventually said, "Yes, I would." I thought that that captured something very special about the power of the physician in these clinical trials, but also the vulnerability of the patient, and I wanted to explore that.
I also talk about some people who consent to the trial, but I don't know if they're giving informed consent. I got really interested in the difference between consent and informed consent, and how patients out there may say yes to something because their doctor is asking them to and they feel like they may not get good medical care if they say no. Again, this power dynamic is unsettling to a lot of people and is one of the reasons I included historical background in the book. I wanted to mention how doctors were once allowed to police themselves and allowed to draw up trials and conduct trials without any oversight. I wanted to show why that is such a fraught endeavor and a dangerous thing, and why we need things like an Institutional Review Board (IRB) to provide oversight. I also add how the IRB can be a needle in the side of a researcher like me.
Topol: Right. Are there any other patients from the book you'd like to mention?
McCarthy: Yes. One was a schoolteacher in Westchester, and she had a MRSA infection on her body. All that she cared about was getting back in the classroom more quickly. I thought it was interesting that a unique aspect of this antibiotic was that one dose stays in your system for weeks, allowing you to go back to work more quickly; you don't have to stay hospitalized, receiving an intravenous treatment. She was not thinking about her skin or her fever or her infection; she was thinking about these students, and it almost made me emotional and get choked up thinking about how the patients that I walk in to see every day have so much on their minds, and how powerful that experience can be. You think about clinical research and often it is about Excel spreadsheets and consent forms and protocols. But those unique moments, like sitting at the bedside of somebody who is thinking about a classroom full of children, really turns the whole experience into something unique.
Dalbavancin, in Depth
Topol: I had not heard of dalbavancin before. Where is it now headed?
McCarthy: This is the joy of doing research like this. My hospital had never carried it and was never going to carry it, and then I pushed to do a trial that showed a statistically significant decrease in the length of stay and an improvement in the quality of care in a way that would actually save the hospital money. Just recently our hospital voted to approve it, and we're going to start using a drug that had never been used before. The drug was approved for skin and soft tissue infections, but we're finding that it also has potential for use in bone, heart, and bloodstream infections, so one exciting thing is that we're going to start looking at how it may be used to treat other conditions. That is going to take up quite a bit of my time moving forward.
Topol: What is the indication for its use currently? When would you go to this drug?
McCarthy: We would not use it as the first-line treatment for all patients. If you develop a skin infection, you can often be treated with an oral antibiotic. If that fails, many patients go to the ER and get admitted for an intravenous treatment of vancomycin and stay hospitalized for several days. We're trying to prevent that. We're trying to capture the patients who fail an oral antibiotic and come to the ER looking for a second opinion or looking for help, and we can give them a dose of this drug and then get them back to normal life. I think that is the profound advantage of something like this. The tricky part, when you start looking at it for more deadly types of infections, like a heart infection or bloodstream infection, is that you don't necessarily want to discharge the patient quickly; you want to keep an eye on them. We're trying to design trials where we balance the fact that we can discharge patients more quickly with the need for observation. As you can imagine, that has a number of layers to it and some ethical components that we're wrestling with right now.
Topol: As I recall, vancomycin is used in MRSA [and may be associated with development of] Clostridium difficile and pseudomembranous colitis, which can be lethal. Microbiome fecal transplants have been used as a therapy. What about this drug?
McCarthy: We often use vancomycin but it has a lot of side effects, as you mentioned. It can also cause renal impairment and redman syndrome. We've been seeing that the S aureus in the community is becoming increasingly resistant to vancomycin because it's prescribed so frequently. So, we're trying to introduce a new drug that will capture some of those vancomycin–intermediate susceptibility S aureus and the vancomycin-resistant S aureus, but this is something we have to use judiciously because we don't want to run with this new antibiotic and overuse it.
Complicated Relationship With Pharma
McCarthy: That brings up a very challenging aspect of antibiotic development, which is that these companies spend a billion dollars to get a drug approved and then doctors don't want to use it. They want to use it as sparingly as possible, and that makes the market a very tricky thing for these companies.
Topol: I want to get into the whole relationship with pharma. They have largely abandoned developing antibiotics for some of the reasons you have touched on. And here you are—you work kind of against the grain, paddling upstream to find this antibiotic's utility. What is your sense about biotech, pharma, biopharma, and antibiotic development?
McCarthy: I think this is one of the most important issues in medicine that no one is really talking about. For the past 75 years we have relied on a partnership between the federal government, the NIH, and Big Pharma. The NIH is very good at identifying talented scientists who can discover molecules and then they partner with Big Pharma to bring that drug to market. But we have found that this partnership is dissolving. Antibiotics are not profitable and Big Pharma is choosing to do other things with their time. This is a big problem because just as superbugs are becoming more prominent and more lethal, we are losing the partner who has helped us to make the treatments. A number of proposals are on the table to entice Big Pharma to come back to us and to make more antibiotics. These are called "push and pull" incentives. For example, Allergan is the company that makes dalbavancin and Botox, and they had $3 billion in sales last year. A push incentive would be to go to Allergan and say hypothetically, "Your corporate tax rate is 18% and we'll cut it to 15% if you promise to invest some of those excess profits into antibiotics." By contrast, a pull incentive would be if you said to a company, "If you take the risk, develop a new antibiotic, and it gets approved, rather than giving you 5-7 years of market exclusivity, we'll give you 25 years." This means that they can charge a higher price for a longer period of time and make back their investment. The problem with that is that it drives up the cost of healthcare, and antibiotics are already really expensive.
We're going to be hearing more and more about push and pull incentives. In fact, it's going to become a political issue because bipartisan legislation was just introduced. We're trying to get the government to step in with the DISARM Act. In some parts of the world they are saying that we should nationalize the production of antibiotics. England has been talking about this. The thought is that we should look at antibiotics as a public good, like electricity or water, and disentangle the whole thing from profits and just say, "Let's pool our resources, make these things, and share them."
Colonization of Medical Facilities With Bad Bugs
Topol: You had a really great New York Times op-ed right around the time of the release of the book. It was about the fact that our hospitals are infested with superbugs and something like 5% of healthcare workers are colonized with MRSA. But superbugs are also everywhere. Would you want to comment about this kind of colonization of medical facilities with bad bugs?
McCarthy: Yes, we're wrestling with how to talk about superbugs in our environment. The story became a pressing issue when The New York Times put C auris on the front page. Facilities in New York, Chicago, and other states had this fungus but their hospital public relations departments kind of freaked out and said, "We don't want you talking about this." This was a challenge because I'm an expert in this fungus and I was asked to speak about this quite a lot, and they told me not to. We're trying to figure out how and why we should discuss superbugs. So I wrote this op-ed saying that the story is not going to go away and we can't just say "no comment." We need to educate people and there is a big push now for more transparency. It's challenging because there are people who will avoid medical care if they feel like their local facility is infested with superbugs and they are going to catch something. We don't want that. On the other hand, we don't want to scare people. We're trying to figure out how best to report what we're finding, and I can tell you that it's a work in progress.
I've treated patients with C auris, and the part that got left out of the story is that we cure them. This is not a death sentence. In fact, at my hospital and other top-notch hospitals, we are likely to see more of these superbugs because we have the best diagnostic equipment, the best antibiotics, and the experts who know how to treat them. It should not be seen as a black mark against a facility if they have a lot of antibiotic-resistant bacteria within their walls. How do you convey to the public that that is something we're working on? I wanted my book to be at least a first step in that direction.
Climate Change and the Worsening of Infectious Diseases
Topol: Another related issue is climate change, which is having some pretty drastic effects on healthcare. One of them is indeed the worsening of infectious disease risk. Can you comment about that interaction?
McCarthy: Absolutely. As the environment changes, it often leads to animals living in places that they used to not live, and they have all kinds of bacteria, viruses, and parasites that can now come into contact with humans. I used to study the Ebola virus and Nipah virus, and I would go to these far-flung places where climate change was happening and where deforestation was causing a disruption in the ecosystem and allowing animal-to-human transfer of deadly pathogens. We think that the coupling of deforestation and climate change and some migration changes based on climate change is where the next great pandemic is going to come from. It is going to allow some pathogens to leap potentially from a fruit bat or rat to a human and spread around the globe very quickly.
I spend a lot of time thinking about how climate change will affect us. In fact, the issue of drug-resistant bacteria and microbes has been compared to climate change by some who say that it often gets put out there like something others can deal with, but you yourself don't have any role in. Like when a manufacturing company is pumping out a lot of CO2, that is something someone else is doing. But in fact we all play a role in the rise of drug-resistant microbes, whether it's physicians who are inappropriately prescribing antibiotics, like myself, or if it's a patient who is prescribed 5 days of an antibiotic but only takes 2 days. That allows the bacteria to mutate, evolve, and develop all sorts of resistance mechanisms. This is an issue that we all play a role in, and that is part of getting the word out.
Metagenomics
Topol: I'm glad you've emphasized that. It does not get enough respect and it really needs to be highlighted. We're seeing a revolution in sequencing pathogens. Just last week in the New England Journal of Medicine, there was a report from University of California, San Francisco, and collaborators where brain infections were diagnosed by sequencing metagenomics with cerebral spinal fluid, and, of course, picking up all sorts of misdiagnoses.[2] A limited number of lives were saved, but still it was very impressive. Are we going to be moving to a time where we'll take a sample of body fluid, put it through metagenomics, detect the causative pathogen and not a contaminant, and also get a readout on resistance at the same time? Assuming that we have enough informatics and the bigger information resource to define that. Are we moving to that point in the years ahead?
McCarthy: Absolutely. This is so exciting for me. On Thursday mornings I go to the microbiology lab and spend time with the team there to figure out how they are diagnosing infectious diseases. How are we detecting these things, how are we ensuring that they are not contaminants, and what are we doing in terms of coupling that with identifying resistance genes? We've seen this revolution in many aspects of how we detect drug-resistant microbes, whether it's the MALDI-TOF MS (matrix-assisted laser desorption ionization time-of-flight mass spectrometry), which is using this laser essentially to identify drug-resistant bacteria, or whether it's gene sequencing for some of the viruses. But for fungal infections, the area I'm most interested in, we're often diagnosing them the way we did 100 years ago. For mold infections, it's often me looking under a microscope and saying, "What is the shape of this mold?" and then comparing it to a textbook. In some ways we're making these tremendous leaps and bounds with metagenomic shotgun sequencing, and then in other areas we're very seriously looking under a microscope and saying, "I think this looks like Mucorales but it might also be Aspergillus. Let's take a look at the textbook that was written 5 years ago and compare it." There is certainly an imbalance there.
Topol: Is Weill Cornell starting to do metagenomics for clinical purposes?
McCarthy: We do a lot of gene sequencing that is not reported out to the clinicians yet; it's stuff that we have for research purposes. One of the big challenges we have is that we could report out all of the fungi that are in a patient's nostril, but we don't want this to freak out the physicians because most of those are commensal organisms or colonizers. I hit on the fact that it's a challenge for us to talk to the public about these infectious diseases but it's also a challenge to talk to doctors. A lot of them don't know what to do when they see a readout of 16 different viruses identified in a sample, many of which may have no clinical relevance.
Topol: Right. There is a lot of potential excitement in remedy for some of the issues that we're confronting today, and it's noteworthy how so much of what we do is archaic, as you've pointed out. Historical grounding was one of the great parts in your book before getting into where we are headed in the future.
I want to congratulate you on your excellent book, Superbugs, and also for being a really fine physician writer. We don't have enough of those. Matt, it was great to be with you on this Medscape One-on-One. Thanks to everyone in the Medscape audience for listening to our conversation on this really important topic. We need more emphasis on developing antibiotics, new ways to diagnose accurately and quickly, and ways to deal with and prevent resistance. Matt, thanks very much.
McCarthy: Thank you. It was great to be here.
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