— phone call transcript of Dr. Puxiao Cen’s response to questions on antimicrobial resistance (12/9/2019)
1. The first question is that what do you think is the reason the antibacterial crisis exists?
The antibacterial crisis, superbugs, I would say, I call them superbugs because I want to include bacteria, fungi, viruses, and parasites into all of these superbugs. For the sake of convenience, and for easy discussion’s sake, we are going to focus on the bacteria on this recording. The reason is simple, really Darwinian evolution. Each time an organism divides, there’s a chance of mutation, and mutation will allow the organism to develop new tools to fight against either naturally occurring or a man-made antibiotic. The time that human takes to produce the next generation is about 20 to 30 years, but bacteria only take about 20 to 30 minutes for them to have a whole new generation on average. And you can tell easily how fast they can develop through mutation resistance. And bacteria already coexist with us for a long time. They actually existed way before us on this earth for about 3.5 billion years. And the first time we developed antibiotics was probably merely 60 to 70 years ago. So, bacteria have a lot more armamentarium in their pocket to deal with the antibiotics that would produce man-made. I mentioned naturally occurring antibiotics they exist in the wild. And their resistance to these naturally occurring antibiotics are also naturally existing in the wild. And the resistance can be shared between species. And resistance genes can be even found in ice core or caves that no human ever entered before. And not all microorganisms are pathogens, only very small percentage of them are what we call pathogens when they have the bearing factor that could cause diseases. And it was given out to our immune system to detect and track them down and kill them. Most of the microorganisms are really colonies in our body, the microbiome as we call that. They exist in our G.I. track, our skin, and mucosa, they do a lot of good things and use vitamins helping us to digest food. And they even instruct the immune system how to function properly and they also make natural antibiotics. So, when humans use man-made antibiotics to kill certain pathogens, it’s easy to have friendly fire or collateral damage to take out the normal flora. So, there is a book by Doctor Martin Laser, it’s called Missing Microbes. It’s very much worth reading. The healthy person may walk around with a Staph aureus or even C-diff in their system and may not getting infected. Infections mean they spread deep into our body. So, if these pathogens are really existing on our body – inside our body, not causing diseases, then they’re innocent. We don’t need to eradicate them. And when we have normal immune system, they’re just there. On the other hand, if they start to invade our system and cause infection then we use antibiotics to deal with them. The earliest antibiotic is penicillin. It destroys the bacteria’s cell walls. The whole group is called a beta-lactam. The bacteria are able to produce the resistance by producing what’s called lactamase. They re-shape their molecules so that they can resist the destruction by the penicillin. And there are thousands of genes that can produce different kind of beta-lactamase and they confer resistance to penicillin, and I wanted to say that I am a cardiologist and I have been doing cardiovascular disease for 25 years. I have not been that deep into general medicine. I am not an expert in ID, but I can tell you what I know, and you quickly talk about how the penicillin was discovered. Alexander Fleming in 1928 accidentally discovered penicillin. And he actually was the first antibiotic steward. That means he understands the proper use of antibiotics in order to reduce the chance of antibiotic resistance. It takes about a decade for the penicillin to be mass-produced. Fleming is the first one who described antibiotic resistance. It says, if we use too little a dose or too short period of time to treat a person, then the microbes are educated to resist penicillin. And he even said that the thoughtless person playing with penicillin is morally responsible for the death of a man whose account to penicillin resistance organisms. He already realized that when antibiotics are used, they should be used properly. In 1950s, dozens of antibiotics were discovered and half of the antibiotics that we are using today actually were discovered during that decade. It was a golden era of antibiotics discovery, R&D, and production. By the end of 1960, though, the shift of the pharmaceutical companies was starting to be more toward the lucrative drugs such as heart disease and cancer. But we’ll talk about that a little bit later. In our bodies, how trillions of bacteria are waging warfare all the time? Survival of the fitness really is playing out every day, every minute in our body, they produce naturally occurring antibiotics, but they are able to reach an equilibrium. However, when we develop antibiotics on a mass scale for the first time, bacteria are commonly targeted in our microbiome again and again. And that is producing a lot of collateral damage to the friendly microbiome, which in turn would interfere the proper functioning of the immune system that I have mentioned earlier, some of the microbiome in our body is really crucial in instructing our immune system to function. The gut microbiome itself, the cells outnumber our body cells 10 to 1, and the genes outnumber our genes by 100 to 1. So, we are almost the platform that bacteria are ruling the world.
2. The second question you ask is, how serious is the crisis being over-exaggerated?
I would say we are not talking about it enough. It is estimated by 2050 there will be more people dying from antibiotics resistance bacterial or fungal infection than heart disease and cancer losses. Even from day to day practice, I can see that it’s easy for hospitals under-reporting these problems because even the most sophisticated hospitals, even if they are the expert of treating the most difficult resistant bacteria or fungi, at least the administrators would have a little bit concerned or worried that they could be labeled as an institution that invested with the scary superbugs. And there’s no federal law to say all hospitals have to report a certain resistant superbug. There are so many resistant Enterobacter, C-diff, gonorrhea, T.B., a lot of the staph aureus drugs, they are all resistant when single infections or simple skin cuts, appendix can cause so much infection that can cause death. Even with anesthesia we are able to do surgery making sure patients are in relative comfort during the procedure, but we are not able to control the infections afterwards, then that could mean the end of modern era. We are not able to even change the joint or are doing c sections safely without infection. Patients who are on hemodialysis 2 to 3 times a week are not able to have that done without risking infection. Transplant is out of the window because when you do organ transplant or bone marrow transplant, you have to use immunosuppressant to reduce the strength of the immune system to target the new organ. But at that time, your body is at risk of acquiring infection, the opportunistic infection very easy to spread throughout our body when anti-rejection medications are weakening our immune system. So, without strong and effective antibiotics, when the bacteria are antibiotic-resistant, then we are not able to use the immunosuppressants to treat patients who have organ transplantation. Stem cell transplant is the same thing. On the other hand, when antibiotics are being used indiscriminately, the normal environment of microbiome in our G.I. tract is disturbed. It is associated with a lot of auto-immune disease, allergy, obesity, ulcerative colitis, irritable bowel syndrome, even Parkinson disease, depression. More and more data supporting the diseases have a connection with the interruption of the microbiome in our G.I. tract, partly due to the usage of antibiotics is inappropriate. And there is a U.S. map that I have seen that plotting the spread of antibiotic resistance and plotting the obesity. And it’s amazingly overlapped, that means the places where incidents of obesity are the highest, those are the also the places where antibiotics resistance after the incidents are highest. And it is hard to imagine a post antibiotic era that will essentially be becoming the pre-antibiotic area that 90% of children with meningitis would die and those who survive would live with severe, lasting disabilities, such as deafness, mental retardation. We are not able to treat strep throat that will have more amputation because they are simple infection on their limbs. You see when you watch those movies, the historical movies it would show so many people who are missing a limb, and that is a lot to do not just because of trauma, but also simple infections of their legs could spread very easily and without antibiotics is the only way to prevent the bacteria getting into the bloodstream and causing sepsis and killing a person is to amputate that the limb. So, without effective antibiotics we will live like that again. Simple ear infection of children can spread into the brain and cause death. If you work in the garden and have a puncture wound or some skin infection, it can spread easily. It will just make it very difficult for modern medicine to continue to be a modern medicine. When you cannot do simple surgery, we have very high failure rate with all the simple surgeries. Currently, the most commonly encountered resistance bacteria are the Carbapenam resistant Enterobacter, klebciela, mrsa, some gonorrhea, resistant campalobacter, strep throat, T.B. There are some areas in the New York state that in cases of UTI a third of the e.coli are resistant to Bactrim. Not all hospitals are reporting the resistance superbugs reliably and some of them are afraid that the patients would become scared and patients do not want to go to E.R. that could cause more health hazard when people in the community are scared to seek health care because of their fear of getting an infection of the superbugs. We are really losing the P.R. battle here with the kind of hospitals that have the most expertise that is the most afraid of being labeled as are being infested with superbugs. And many community hospitals may not even have the expertise to make the accurate diagnosis of the superbugs, and they are not under-reporting, they’re really missing the diagnosis. When you hear some places or some smaller hospitals say that they have a very low incidence of superbugs, don’t get happy yet, don’t get too optimistic yet, because they may have just a poor diagnostic skill or expertise to recognize the true incidence of the superbugs.
3. The third question you ask with an ongoing opioid crisis in the United States, in my opinion, do I believe that the antibiotic crisis would reach the magnitude of the opioid crisis?
Well, I’m no expert in either antibiotic crisis or opioid crisis during the election season. I am always surprised by how the lack of discussion of such serious issues that we are facing. Most of the voters would focus on economic development of second most important issue during the election is the national security, so they vote for their personal financial future, jobs, and they vote for homeland security. That kind of issue would attract a lot of tensions, but I would say that superbugs pose a threat to both the personal financial future and national security. And even when voters think about health care, they really think about health care insurance coverage. They are not really thinking about the ability of us are dealing with the superbugs or opioid crisis. So, I would say that we should discuss these two areas a lot more during each election.
4. The fourth question you ask, how much influence do you believe U.S. health care has had on creating the antibiotic-resistant bacteria crisis?
I would say a lot. But don’t forget there is also the whole industry of farming and the agricultural industry is playing a role too. But let me talk about both even though you just ask about the health care section. First, the health care, the research and development (R&D) of antibiotics. The pipeline is dwindling really to the point that it’s trickling at this time. When the usual discovered patent for the molecules will be only 20 years and the research in development will usually should take about 11 years. And that means when if this product is successfully brought to the market, it may have only 9 years to recoup their research and development expense. Because research and development are already taken 11 years out of that 20 years patent. On top of these concepts of antibiotics stewardship, when you prescribe antibiotics, you usually prescribe I’m talking about outpatient oral antibiotics is about five days to 10 days. When you compare that to a lifetime of a long term usage of medications for say, hypertension, diabetes, there are many chronic diseases requires a long term therapy, whereas each infection you trying to use antibiotics for a short course enough to cure the infection but not too long to create or encourage resistance. Pharmaceutical companies already looking at naturally short course of each time their medications are being prescribed and also the more and more stewardship that is here now in each of the health care institutions. The health care institutions, such as hospitals and nursing homes started to use stewardship or antibiotics steward because they try to limit the over-prescription of the antibiotics. And they try to limit the emergence of resistance or superbugs in their institution. And in general, it takes about a billion dollars to have one medication goes through R&D process over that 11 years and successfully being brought to the market. And naturally pharmaceutical companies have to consider the future cash flow against an R&D cost. Antibiotics typically would cost negative 50 million per antibiotics discovered, and they do not want to have such poor investment. And it’s understandable that they turn their focus toward more chronic illness or the diseases that people who willing to pay more for. For instance, a person would feel reasonable, or they think the price tag of a special chemo medication that sometimes we just prolong their life by a few months, they still think it’s reasonable to pay for thousands and thousands of dollars for those cancer medications. But they would think that paying more than a few hundred dollars for antibiotics is ridiculous. So, in general, the public would not accept a higher price tag for antibiotics. So even if you convince or you allow or the government allow the pharmaceutical companies to increase the price of their antibiotics in exchange for a willingness to research and produce them, the market would not accept that. Antibiotics was first started to be reproduced in late 1940s after world warⅡ, the first was penicillin-like I mentioned earlier, and during 1950s to 90s, per year, there are approximately three new products produced, but now not even one new every other year. So, it is a whole six-fold reduction of new antibiotics that is being produced. And at the same time, the old antibiotics are being withdrawn or becoming obsolete, two times of that of the discovery of new antibiotics. So, the arsenal is reducing rapidly over the past 15 years in fighting against infection. And this rapid reduction of the new antibiotic pipeline can be explained by several ways. One is that the low hanging fruits are picked already. The second reason is that the large amount of resistance if you use antibiotics to sufficiently eradicate an infection you may need to use a very large dose, but this large dose may not be safe for human. It may be strong and killing bacteria in the petri dish or agricultural environment but cannot be used in health care. Or certain antibiotics are strong effective killers on the petri dish, but when you try to produce into a pill or tablet or intravenous form, it is difficult to be delivered to the target organ or area to fight infection in the human body. And after facing all of these difficulties, even if a pharmaceutical company is able to produce an effective antibiotics, the current medical logic is that to hold this new drug in reserve until there’s crisis, because we don’t want to use a very valuable new antibiotics to treat the easy infections, because the more you use it, the faster the resistance will occur. So, you trying to save it for serious infection, then you can imagine the drug company would not be for sale, these antibiotics in a large scale, the large amount. And they may not be even used right away, whereas when you produced a cancer fighting medication the day is approved, you can start selling it the holding the most valuable and newest antibiotics in reserve would eat up the 8 to 9 years of patent time easy. Remember the patent to new molecules for 20 years and in 20 years about 11 years are being already used in the research and development phase. So, after the clinical risk, first the basic research that the bench research and then the clinical research of phases 1, 2, 3, then the new drug will have only about nine years of the patent after its approval to recoup the money, and now you’re holding it in reserve. Then every day the clock is ticking every day before it becomes generic. And therefore, the antibiotic stewardship or the appropriate medical answer toward a delayed resistance is by reducing the frequency of usage of these strong antibiotics, but it is a terrible, terrible business idea to the drug companies. So, summarizing what I said about the reason for current lack of new antibiotics is two folds. One is by the end of 1960s that the drug company shift their attention to more lucrative drugs such as heart disease and cancer, especially after Nixon declaring on war of cancer in January 1971, the new national cancer act. The second reason is the very recognition of the antibiotic resistance. The more we realize all antibiotics, no matter how strong they are, it takes about 5 years for resistances to occur. It always happened and the drug companies know that they have only that short period of time to use this drug and to sell this drug before it becomes useless due to resistance yet. During that period of time these new medications are mostly held in reserve by hospitals by the antibiotics steward of the hospital, which are usually doctors or PharmDs or nurse practitioners, they are doing a good job in preventing the new medication being prescribed too much overprescribing new antibiotics can, of course, easy to treat the infection right now, but encourage resistance occurring in the institutions. So, it’s the institutions’ interest to prevent or reduce the usage of the new antibiotics. So the pharmaceutical companies know this, and they stay away more and more from the antibiotics R&D. Regarding the day to day overprescribing antibiotics to treat a common cold when it’s viral infection that sometimes patients are so miserable they really hope that the doctors would prescribe some antibiotics for them just in case there is bacterial infection superimposed on the original viral infection then there naturally a very common practice no matter how much doctors try to not prescribe the antibiotics to a patient with viral infection, but sometimes patients really ask for it, and when doctors themselves are not able to convince the patients, or they are not sure really if there is, bacteria are superimposing the viral infection, they prescribed the antibiotics. If it is really a bacterial infection, the patient may erroneously take only 2 to 3 days of it violates when they feel better to stop the medication is supposed to take in this prescribed 5 days or 7 to 10 days course. So that reducing the duration of the antibiotics usage on patient’s part encourages resistance. And these resistances would flush down to the toilet and it from patients’ feces or urine and flush down the toilet and get into the sewage system and go into the soil, but the contaminated environment. And if you include the drug manufacturers in some third world countries, such as China or India, they may not have a very strong environmental organization to regulate their factories, or the factories are not observing the law or the regulations that much so they can have massive amount of antibiotics being flushed down to the soil to the river. And when these resistance genes are in the rivers and soil, they are shared among the bacteria and fungi of themselves. And to the point that not only patients but healthy people who are colonized with this resistant bacteria are everywhere and these switch system, this farming practice this drug producing factories, they harm the people living in their community and far beyond their community because of the river and in some countries, again, the third world countries, the hospitals may not even have antibiotics steward who are in charge of the proper usage of antibiotics in that hospital or nursing home. The contribution from the health care people in the spread of antibody resistant superbugs are not small but compared to the commercial agriculture farming and drug-producing factories, it’s not a large scale. And meat-producing animals use a lot more antibiotics. There are some orange groves that would use syphilis or tuberculosis drugs to cultivate the oranges to kill the microbes in the soil. There are powerful lobbies working every day to maintain the usage of such antibiotics, such as the syphilis drugs or TB drugs in growing oranges. There are fungicide being used in the gardens in the Netherlands or central America. When I went to Ecuador, I saw the rose gardens are using antibiotics. The health care overprescribing compared to these are really a small scale, and there are some diseases such as the dermatologists are using antibiotics to treat with rosacea or there are some infections say in the spine they need to use lifetime suppressive low dose of antibiotics to prevent the spread of the infection from the spine to somewhere else. The cystic fibrosis patients or a burn patient who will need long term antibiotics. So, there are conditions in healthcare that we have to use antibiotics for the long term, not all antibiotics being prescribed long term is inappropriate prescribing.
5. The fifth question is how much influence you believe the U.S. health care system has had on creating the antibiotic crisis.
I think I already answered some of it above.
6. And the next question you ask is the over-prescribing antibiotics is a significant contributor to the bacteria of resistance crisis?
I also answered that above, but let’s talk a little bit more about the U.S. health care system if there’s a way to the regulation changes or strategy to help to alleviate this crisis. Well, one is what I talked about the stewardship, each hospital nursing home, skill nursing facility they should have antibiotic stewardship to oversee and prevent the overprescribing or using too strong antibiotics when it is not necessary when a lower tier antibiotic can do the job. Another is that when I talked about the first pharmaceutical company’s resistance or reluctance in spending money on the R&D to produce antibiotics. There are many regulation alternatives or strategies that are being discussed at this time. One is public funding or giving pharmaceutical company tax incentives. There are many potential antibiotics there can be researched upon. It is just not mature enough to be used in clinical trial. We just need some drug companies take on the task. But there is a proposal is called social subscription that is to have global collaboration between U.S. and E.U. to share their new development and have a subscription that means that the drug companies can have access to those preliminary medications so that they do not need those companies do not need to spend money at very basic level of research. In that way, the drug companies will not only stay in the therapeutic space of the medications that are financially rewarding to them such as heart disease or cancer drugs. If they are able to have access to those preliminary drugs, then they save a lot at the early stage of research. And even though if they’re not selling 10 or 20 billion per year like heart disease drugs or cancer drugs, they may be satisfied with selling a few billion dollars a year on these antibiotics because their R&D is not that heavy in terms of investment. But soon after this proposal was mentioned, the drug companies say that they probably would need even more incentives not just these social subscriptions but the tax incentive, for example, to use is that when they sell a blockbuster medication, if they can be taxed less, they are willing to use those saved taxes to the antibiotics R&D. So, the government also is using this as an enticement. Right now, the government’s participation in terms of funding in new drug development is really not a brand-new idea. There are orphan drugs act that have produced hundreds of drugs that using the tax incentives that the government will save the drug companies about 50% of the expense toward face to face three clinical research. These monies are covered by public funds, the NIH and many universities of their grants are using this to produce many orphan drugs. These are successful examples in producing certain rare cancer drugs are not still very welcomed by drug companies to produce antibiotics. Because the elephant in the room that is called a antibiotics resistance. It only takes it on average about 5 years or sometimes 8 years to have antibiotics resistance. And drug companies still feel that not able to have a long enough time to regain or to make enough money to cover the R&D investment. I also talked about all institutions, good institutions, responsible institutions when they use antibiotics, they have a firewall or stewardship that limit the antibiotics over-usage. So far, not a lot of strategies are effective enough to convince the drug company to produce antibiotics. And therefore, there’s another voice saying that we should nationalize antibiotics production because antibiotics are a public good just like water and electricity. And a society, a government, a country or the whole human race should pool the resources together to make the antibiotic production a government project no longer in the private sector. This naturally is not welcomed by people who are suspicious of the government in general. Most of the time, people do not. At least in America, people do not want drug production becoming a nationalized industry because it’s being seen as inefficient or even counterproductive. Other regulations include giving tax incentives to the companies that research new diagnostic techniques so that they can enable a lot of doctors to make diagnosis make accurate diagnosis of an infection rapidly as opposed to nowadays we are still using most of the time we are still using old-styled way of culturing bacteria or fungi on the petri dish and then give these cultured organisms different antibiotics to test their sensitivity or resistance. And these process takes a few days at least. And these are the time that patients and doctors do not want to wait. The symptoms are so severe, and threat spread over 24 hours to 72 hours is so grave that patients and doctors want to go ahead to prescribe empirically prescribed broad-spectrum antibiotics to cover or possible organisms first. And this naturally encourages a lot of antibiotic-resistant organisms’ occurrence. So, the diagnostic techniques are the front that we really need to improve. Hopefully that would be a day that is just like doing a CT scan or MRI of seeing images of the part of our body we will be able to use immunology or more of the molecular way to diagnose organ microorganism infections. So, their proposal and government should provide heavy tax incentive to the high-tech industry to produce those diagnostic methods, not just a drug company to produce antibiotics. And the last proposal is that helping the researchers to see the needles from the haystack. That means when I talked about how prevalent the naturally occurring antibiotics exist in the soil in the water system. We need a more effective way to find these naturally occurring antibiotics. The current way of finding them out is too slow and hopefully using the big data or artificial Intelligence. They are able to sort out the useful antibiotics materials that occur in our natural environment to use them or gene editing to make them useful medications. And their proposal of the government doing their part of the job and when they find something that are hopeful then they provide to the drug companies free of charges. And earlier when I mentioned that in general there’s under-reporting of the superbugs from the hospitals are in the campaign trail, I heard one candidate mentioned that there should be a federal mandate for all hospitals reports superbugs because currently, the regulation varies from state to state. So, there’s a lack of transparency. And the CDC and NIH are not able to get sufficient information in the occurrence of the superbugs and, therefore, not able to devise a strong containment strategy and protocol. All of these above-mentioned potential regulation or strategies really requires a strong political will in a public discussion during this campaign season on the campaign trail. I talked about antibiotic-resistant superbugs really from the perspective of a first-line medical worker, a doctor who’s seeing patients and doing bedside patient care day in and day out for 25 years. However, I am a cardiologist, and my expertise is in cardiovascular diseases, but since then, superbugs are such a major threat to our overall health and survival of human beings. And if we don’t deal with it effectively and soon enough, then we will be looking at by 2050, there will be more people dying from drug-resistant organisms than from heart disease and cancer. And it’s a serious problem and we should have a stronger political will to devise and have a collaboration between countries to deal with this problem so that we don’t get into this post-antibiotic era when simple skin infection, simple injury or simple surgery can mean the death of a person because of the infections can spread so rapidly.
岑瀑啸，出生于中国广州医学世家，1992年在中山医科大学六年制医学系全英班毕业后赴美，并于1995年到1998年在当时附属于纽约大学的Lenox Hill Hospital任内科住院医生，之后的1998年至2001年，在费城的天普大学医院（Temple University Hospital）任心血管专科住院医师兼内科带教导师(Clinical Instructor)。2001年起在佛罗里达的奥兰多AdventHealth医院（原名Florida Hospital）任心血管/心移植专科医生，并在2003年获得FACC（Fellow of American College of Cardiology）称号。除此之外，她拥有Creighton University的医学伦理硕士学位，是AdventHealth医疗系统临床医学伦理委员会成员。岑医生著有杂文集《医道凝眸》和《医者阅世》，分别在2013年和2015年由天津人民出版社出版。