9UNP1272_Craig_Kent_Rick_Page_WordPress

- So, welcome to Mini Medical School. My name is Craig Kent. I'm the chair of surgery here and one of the Mini Med deans. And my compatriot there is Rick Page, chair of medicine.

We're real excited that all of you could attend tonight. Usually our real dean, the dean of the School of Medicine, is here to give you an early introduction, but he had to be away tonight. But it gives us a chance to brag a little bit as Mini Med deans because I think there are, what, about 160 students per year in the School of Medicine class, and, if I'm looking around the room, I think we have about 500 students in our school of medicine. We'll send him that message that he needs to pick up the pace. So, how many of you are here for the first time? 

Okay, a few of you. And so I assume everybody else has attended another one of our med school classes. So this is our fifth year. In fact, it's the completion of our fifth year. So our third session, fifth year. That means that many of you are going to graduate. 
(audience laughing)
 But the fact that some of you have been here the entire five years suggests that maybe there's a problem, right? Because you're supposed to finish medical school in four years. So it's all right. 

If you want to keep on coming, we'll keep on teaching. We have an absolutely fantastic program tonight, and I think you'll really enjoy. It's all about infectious disease, bugs, microbes. And all you have to do is watch the movies and television and the fear that we all have that some day the world will come to the end because of microbes. Well, there's a lot to that, and I think tonight you're going to learn a great deal about infectious disease. The other point that I wanted to make is that one of the reasons that Rick and I developed this program in the first place is that we think UW is an absolutely fantastic place. And we were afraid that you didn't know how fantastic we in fact are. And the truth is that our School of Medicine and many of our faculty at our School of Medicine are nationally known for their work, their research, their abilities clinically. And what we wanted to do is have you learn a little bit about medicine, learn some practical things that I think will help you in your daily life, but also to show you the strength we have at UW. And I think by the attendance that we have here tonight and the success we've had over the past few years, we've been quite successful. 

In any event, we should get on to the program. So to introduce our speakers, Dr. Page.

- Thank you. Well I want to... 
(audience applauding)
 Thank you.

I want to join Craig in welcoming you and it's exciting to have you here and it is exciting that we've gone five years. But if it makes you feel any better, actually we have an MD PhD program. And it goes seven, eight, nine years sometimes. 

So we can just keep going, and you don't have to feel like you're red-shirted for one year. The fact that Dr. Golden, Dean Golden, isn't here does give us one opportunity to brag about the dean. We normally he introduces us, and, as Craig mentioned, this Mini Med got started because we were so impressed by this place we wanted to help get the word out. And it was Dean Golden who recruited both of us. And we had pretty good jobs before, but the opportunity to come to Madison and to lead departments in this School of Medicine and Public Health was irresistible and we've never regretted that and it's been a great time here and a great partnership with Mini Med. Before I go on with introductions, I do want to mention one other special thing. You may have noticed that lights are a little bit brighter here. We have a relationship now with Wisconsin Public Television, and they are actually photographing and recording this and this will be in the University Place. And you may remember when we did the session on Cancer: The Emperor of All Maladies, that was cross-marketed with that wonderful program series that Wisconsin Public Television had on at that time. 

The other thing I'll mention is a new radio station, WMUU, which specializes in spoken word, progressive, and social issues as well as science, 102.9 is a new station and they're actually recording us and they're going to be focusing on science and medicine and including Mini Med audio in their programming. So that's kind of neat, and welcome to both organizations. Now, I have the pleasure of introducing the four speakers today, and they are in the Division of Infectious Diseases in the Department of Medicine. But as you know, Dr. Kent and I, we do this to highlight all of the School of Medicine and Public Health. But, actually, the experts in this specific area, the topic of the evening, are primarily in internal medicine and infectious diseases. But I will highlight the fact that Dr. Andes has an appointment in med micro, a basic science department, and Dr. Safdar, who you're going to be hearing about and from soon, has appointments in engineering and population health sciences. So this really is still a multidisciplinary presentation today. 

So it's really my pleasure now to introduce the moderator for tonight's session, the person who's going to take us through the evening of infectious disease, and that's David Andes. David is a graduate of St. Louis University and the University of Missouri. And just after that time, he came north and came to Madison and has never left. He went through our residency program, our fellowship in infectious diseases. He trained with a number of people, including Dr. Maki and Dr. Craig, and now is leading the Division of Infectious Disease. He has too many honors to mention, but I should highlight that he's a member of the American Society of Clinical Investigation, which is a very prominent scientific group that one is elected to and all of us aspire to be involved in. And he also recently was elected chair of the Infectious Disease Society of America, the organization that represents infectious disease specialists. 

So he's vice chair, and he'll be chair of that organization next. So there's no more appropriate person to be leading tonight's discussion and being actually one of the speakers about some exciting work of his own than Dr. Dave Andes. Please join me in welcoming him. 
(audience applauding)
- Thanks, Dr. Kent and Dr. Page and certainly the audience, for the opportunity to present some of the work that we're excited about going on on this campus. As Dr. Kent mentioned, we're going to talk about the superbugs that you hear about termed in the lay media. 

And to put that into context, imagine that you present to your clinician with a cough and a fever and unfortunately you're diagnosed with pneumonia and admitted to the hospital. One or two decades ago, the treatment of that might have been fairly simple. You would have expected to receive an antibiotic and have fared well. And as I mentioned, one or two decades ago that might have happened. But that's not the case these days. In fact, every day in our hospital we see at least one patient with an infection for which we do not have an effective antimicrobial therapy because of the development of resistance. And what you're going to hear about tonight is the scope of that problem and from a variety of investigations on campus that are targeting the prevention and eradication and new antibiotics to treat these drug resistant infections. Our first speaker is Dr. Dennis Maki. Dr. 

Maki, as many of you know, is not only a university gem, but a world renowned clinician, teacher, and scientist. Dr. Maki, we're fortunate enough, each of the subsequent speakers is fortunate enough to call him our teacher. And Dr. Maki is going to first introduce you to the scope of the problem of antimicrobial resistance and then just touch on some of the path-breaking discoveries that he and his group have discovered to prevent contracting these drug resistant infections. So, with that, Dr. Maki. 
(audience applauding)

Thank you very much.

We're going to cover six areas tonight, and I'm going to cover the first two. 

I'm going to address two issues: the magnitude of the problem with antibiotic resistance and what can we do to prevent infections in the first place. If you prevent antibiotic resistant infections, you don't have to try and treat them.

Now, exactly what are antibiotics? We've used this term, and it's very important in science to be as precise as possible to try to be as accurate in what we mean in our words. And you see the term antimicrobials. Antibiotics and antimicrobials are basically the same thing for all intents and purposes, and we'll use them interchangeably tonight. Antibiotics started with this serendipitous discovery approximately 75 years ago. Alexander Fleming was certainly not a knight at the time he made this discovery. He was a relatively unknown academic laboring in the microbiology lab doing research on staphylococci. And you see here a plate, and these colonies on it are staphylococcal colonies. 

The plate was left out over night, and the weekend came up, it was open all weekend. And when he came in on Monday, he noticed this big colony, and we know that's a fungus. There's fungi in the air and fortunately, they pose little risk to healthy people, and we see them on plates all the time.

But Pasteur said, "Chance favors the prepared mind." And Fleming noticed something very important. There's no staphylococci growing here. There's something in this fungal colony is producing a substance that's inhibiting the growth of staphylococci. Might this be of utility as a therapy. Well to make a long story short, they quickly extracted what that stuff was. It got called penicillin. 

This was how penicillin was discovered serendipitously. And what happened?

He met the king of Sweden. 
(audience laughing)
 He got a Nobel Prize.

That was the beginning of antibiotic therapy. It took nearly 20 years until they could produce penicillin in adequate quantities to treat infections, and that occurred right about the time of World War II. Now, antimicrobials are unique drugs that have a selective capacity to inhibit bacteria, either the metabolism of the organism or the capacity of the organism to reproduce. And bacterial cells are different than mammalian cells, and the drugs that will inhibit bacteria may not have toxicity for human cells. That's the whole principle, then, of antibiotic therapy. 

That selectivity.

However, antibiotics have two downsides They can profoundly alter the normal flora in our body. We're going to be hearing about that later on tonight. And the organisms are adaptable. They can mutate and become resistant to the antibiotic. And the resistant organism can then spread. Well, since Fleming, in the early 1940s, we have come a long way. We have over a hundred anti-infectives of various types. Effective against bacteria, against fungi, against rickettsia, mycoplasmas, tuberculous organisms, and even viruses. They've served us extraordinarily well. 

There's probably no class of drugs that's had a greater impact on health than anti-infectives.

It's only propitious when I talk about antibiotics here to acknowledge a person who's had an enormous impact on antibiotic therapy globally over the last 40 years. This is Dr. Bill Craig. Bill was a member of our division, one of the founders of the Division of Infectious Diseases at the University of Wisconsin. And Bill died unexpectedly earlier this year. Bill made a very important discovery that was equally important to that of Fleming. He hypothesized that how we used antibiotics, how we dosed them, might influence how effective they are. And in a series of very simple but elegant experiments and very sophisticated mathematical analysis, he was able to show almost all antibiotics fall into one of two classes. And the bottom line was he showed that certain antibiotics had to be dosed in very large doses not very often, and others needed to be dosed in much lower doses very frequently. 

And if you followed those precepts, the patient would be more likely to respond, the organism would be less likely to be resistant to the drug. It was a field that he called pharmacodynamics. To make a long story short, that was only 30 years ago. There I did a Medline search. There were 85,000 papers on pharmacodynamics in the world literature through the present day to day. He opened a whole new field of inquiry. The impact that that has had on antibiotic therapy around the world has been profound. And he was a true giant in the history of this medical school and this university, and we miss him very badly. Now an important question anybody might ask about antibiotic therapy is, how important is antibiotic therapy? Does it really make that much of a difference, since we've got good immune systems, most of us. 

Well, let me show you some data from the pre-antibiotic era. What if you were unlucky enough to get a pneumonia? This is an X-ray. And that patchy stuff you see down here is inflammation and infection in the right lower lobe of the lung. If you got a bacterial pneumonia in the pre-antibiotic era, you had a one in three chance you were not going to survive. Today, 95% of patients with bacterial pneumonia survive.

What if your child developed bacterial meningitis? A frightening infection. Devastating infection. Bacterial meningitis in the pre-antibiotic era was fatal 98% of the time, and the survivors were often left severally impaired neurologically. 

Today, 90% of children with bacterial meningitis survive, including this child. This child survived and did very well. Endocarditis, an infection of the lining of the heart, a heart valve. You're seeing the inside of the heart. That red clump is a clump of bacteria growing on the lining of the heart. Can you think of any more invasive infection? In the pre-antibiotic era, endocarditis was uniformly fatal. Nobody survived. It was a fatal infection. Today, 80% to 90% of patients with endocarditis survive and have a good outcome. 

Tuberculosis, hundreds of millions of people around the world are infected by the tubercle bacillus. It's one of the leading causes of death due to infection globally. In the pre-antibiotic era, one in three people who got tuberculosis died. Today, 98% survive and do well. So I hope I've convinced you anti-infectives have had a huge impact on our capacity to treat serious infections. In 1970, one of our most esteemed surgeon generals, William Stewart, who commissioned the first surgeon general's report on smoking, was quoted as saying, "The US is ready to close the book "on infectious diseases as a major health threat." Wow.

Unfortunately, he wasn't right. Infection didn't go away. It became a major problem. 

More patients died due to an infectious disease around the world every day than due to cancer or heart disease combined.

The second point is that antibiotic resistance has come out of the blue over the last 25 years to become a huge issue, and antibiotic resistance now is not an exception. It is not a rarity, as it was when I started my career. It is now the rule.

How does this occur? You're seeing a schematic of a bacterium there, and if there's a mutation in the genome of a gene that is the source of encoding a protein target of an antibiotic, if there's a mutation in that gene, whether it's an enzyme or a structural protein, the organism becomes resistant. Mutations can occur because there's large numbers of bacteria, but they're not very common.

There's something else. If the resistance occurs in one organism in a huge population of 10 million bacteria, it can't compete. It'll die out. 

Unless there's antibiotics that are present. Antibiotics being present allow the resistant organism a survival advantage, and they can become the dominant organism in the population, and that translates to an infection caused by a drug resistant organism. Now, there's one other thing that happens with bacteria that's very insidious and quite striking, and that is you can have a resistant organism that arises, but it turns out that organisms share their genes. The genes for resistance in one organism can be transmitted to another organism, even organisms of entirely different species. This is called resistance transfer, and it turns out it's a very common mechanism of resistance, and it's part of the reason we're seeing as much resistance as we have. So, the most important thing here is that antibiotic pressure allows organisms to have a survival advantage. It's literally a Darwinian evolutionary survival of resistant organisms that become as dominant as they have today. And what the studies have shown, in this study Dr. Safdar and I did a number of years ago, we found that antibiotic pressure is the single most powerful predictor of getting infected by resistant organisms. So, we want to use our antibiotics very carefully, as you're going to hear later on tonight. 

A little bit about the organisms that cause resistance. We have resistance in almost all of the major pathogens we deal with, but this organism has really been the super-pathogen: Staph aureus. Many of us have had a boil in our lifetime called a furuncle. It's a staph infection of the skin. When it's caused by staph that's resistant to methicillin, a class of drugs that's most useful for treating staph, we have what's called methicillin resistant Staph aureus, or MRSA, and most people have heard of MRSA. This is a boil of a surgical wound. This is a patient who had open heart surgery for a coronary bypass and replacement of an aortic valve. They had to open up the sternum. It became infected by MRSA. This infection has a 25% mortality. 

It is a devastating infection, and it occurs in about 1% to 2% of patients who have open heart surgery in many centers. But we've made a lot of progress in protecting patients from MRSA, as we're going to show you. There's still up to 100,000 MRSA surgical infections a year in this country. MRSA was almost unknown as recently as the 1980s, and then it took off. It was thriving in Europe and Australia and many parts of the world. Over the last 20 years, MRSA has become the rule rather than the exception. Two-thirds of all hospital staph infections are now MRSA. What's even more alarming now, two-thirds of all community acquired infections with staph are MRSA. More patients now are dying due to MRSA infection every year in this country than die due to breast cancer. That's a statistic I think many people are not aware of. 

Clostridium difficile, which you're going to be hearing more about tonight is perhaps a quintessential multi-drug resistant organism, and rates have risen strikingly. We're pushing 500,000 to a million cases a year. And we have very resistant strains. The morality of C. difficile infection has increased four times in the last 20 years because of very virulent strains that have been selected out. And we now are seeing strains of gram-negative rods coming from Asia that are resistant to all of the antibiotics in our armamentarium, except for two older antibiotics. Tuberculosis resistance has become a frightening concern. In many parts of the world, as many a third of the tuberculosis cases are resistant to the standard drugs, and it is very challenging and very expensive to treat resistant tuberculosis. It can cost 50 to 100 times more than to treat sensitive disease. I hope I've convinced you resistance is a big deal. 

It is a significant problem. World Health Organization is now starting to mobilize resources to try to deal with it on a global scale. The downside beyond resistance being a problem is that the antibiotic pipeline is drying up. You're going to be hearing much more about that tonight. Fewer and fewer new drugs are coming down the road, and we are facing the possibility of treating resistant infections that will have no antibiotics to treat. We always have something, but we're down to maybe one or two final last drugs in many cases now. Now, can resistance be controlled? Are we doomed? And I'll say unequivocally, no, we are not going to be doomed. Resistance can be controlled. 

Let me show you tonight how we can do it. It starts off with better antibiotics, prevention of hospital infections, antibiotic stewardship, reducing antibiotic pressure, and new biologic approaches, which you're going to be hearing about. Now, what happens if you're in a bad accident going home tonight? If something really bad happens to you? 
(audience reacting)
 You're going to hope you get to a good medical center, such as the one here. And you're going to probably spend the night in the ICU. And you're going to get... But if you're awake and you know where you are and your blood pressure is stable and your oxygen levels are good, an excellent chance with modern day healthcare you're going to survive and have a good outcome. But what happens if you get an infection? 

Because, in the ICU, you're extraordinarily vulnerable to ICU acquired infection. This is a germ's eye view of an ICU patient. You see a tube. They see an opening. Intravenous catheters are essential for giving fluids and blood and monitoring blood pressures and monitoring exactly how the heart is working. They're absolutely essential, but they pose a risk of bloodstream infection. We put urinary catheters in critically ill, unstable patients to monitor the urine output, or perhaps they can't urinate because they have a neurologic condition such as a stroke. This causes a risk of infection. The organisms travel right up the tube into the bladder. If you are in respiratory failure, you've had severe trauma, or need surgery, we're going to have to intubate you, put a tube in your trachea and put you on a ventilator to breathe for you. 

This has saved millions of lives worldwide. The capacity to mechanically ventilate patient's in a respiratory failure. But that tube is a direct conduit to the lungs and the risk of ventilator associated pneumonia that has almost a 25% mortality. And we've talked already about the risk of surgical site infections. I'd like to show you four studies we've done in the last 25 years that we think have made a difference for protecting patients from infections acquired in the hospital. And half of all antibiotic resistant infections are caused by organisms acquired in hospitals or nursing homes. So, infection control is fundamental. What we now know is that many of these risks as organisms are readily transmitted to the patient on the hands of healthcare workers, and even hand washing may not eliminate all the organisms. Why not put on sterile gloves and gown as a barrier to prevent transmission, unwitting transmission, between a patient who has an infection and one who doesn't? This is a randomized trial that took us almost three years to do in the pediatric ICU at University Hospitals. 

We did standard care versus barrier isolation. At the end of the day, we found a 50% reduction, that's a huge reduction, in infections, especially in staph and pseudomonas infections. There was no evidence it had any negative impact on the care the child received. The longer the child was in the hospital, the greater the benefit that they got from barrier isolation. This is now being used in many hospitals around the world. Intravenous catheters and intravenous fluids are essential for the management of many, many problems in healthcare. We couldn't survive without infusion therapy. And these catheters are essential, but a big catheter like this one sits right down in the big veins next to the heart. It's very important in many settings, but it poses a risk of bloodstream infection. There's 200 million IV catheters used in this country every year. 

That translates to almost 200,000 device related bloodstream infections. Studies that we and others have done over the last 15 to 20 years have shown that the most common source of the organisms is not from in the hospital. It's the organisms on the skin of the patient right around the IV catheter that's sitting in the bloodstream. And we do molecular typing to prove this. Why not get a better disinfectant to clean the skin before we put in the catheter? The standard of care for the last hundred years has been alcohol or iodine, an iodine based solution. It's brown, it smells strong, should be great. Unfortunately, we were getting hundreds of thousands of bloodstream infections. Chlorhexidine was a new chemical disinfectant that came available about 40 years ago, but it really didn't get any traction in North America. And we did this study about 20 years ago. 

We randomized patients in our trauma unit, high risk patients, to have alcohol and iodine disinfectant or chlorhexidine used for disinfection of the skin and for cleansing the site around the catheter every other day. We were astonished to find a marked reduction in bloodstream infections with the use of chlorhexidine. I thought that the world with throng to use chlorhexidine when we published this paper. Nothing happened for 10 years. It took 10 more studies until people believed maybe this is something real. Literally overnight in 2000, the US embraced chlorhexidine. It has become the standard of care. In fact, there have been over a thousand studies of chlorhexidine since we published our first study, and they have shown it's effective for preventing surgical infections. We do total body bathing of patients in the ICU. Reduces the risk of ICU infection, especially with resistant organisms. 

If chlorhexidine is so good when you cleanse the skin, why not put this little disk it's addressing, which is saturated with chlorhexidine, right around the catheter when we put it in to maintain a high concentration of chlorhexidine on the skin and prevent organisms from growing back and invading the catheter site? In this study we did about 15 years ago, we found a 60% reduction in bloodstream infections. This little disk cost $4. It can be left on for a week. It cuts the risk of bacteria by two-thirds. Multiple studies have now been done of this technology. It's now being used almost universally around the world. It's had a huge impact. The last strategy would be this is a scanning electron micrograph of an infected catheter. This blob here is a staph growing and advancing on the surface of the catheter. 

So, the staph is on the surface of the catheter. Why not make the surface of the catheter resistant? Incorporate an antiseptic into the surface? Well, this is the first study of an antiseptic coated catheter. We worked with a company that developed a catheter that has impregnated with chlorhexidine and silver sulfadiazine, and we found it reduced the risk of bacteremia 80%. There have now been over 50 studies of anti-infective coated catheters. The bottom line is they work. They made a big difference. If we look at the guidelines, the national guidelines that are now used for prevention of IV catheter related infection, we wrote the first draft nearly 30 years ago. There have been now five iterations. 

If we look at the fundamental five control measures, four of the five are based on research done at University Hospitals over the last 35 years. And how have we done nationally? Let's look at bloodstream infections from catheters. Over the last 20 years, we dropped the risk down to one to two per thousand catheters. That's a huge reduction. That is a real progress in protecting vulnerable patients from infection. So we've come a long ways, but we have the potential to do much better. Now, before I turn over the mic to the next speaker, I want to acknowledge somebody who is here tonight and express our gratitude. Steve Skolaski, who is the president of the Rennebohm Foundation, is here tonight, and Steve and his foundation generously donated a large gift to the infectious disease division about 15 to 20 years ago. The next three speakers benefited from that training. 

They've gone on to distinguished careers. Our infectious disease division has increased threefold in that time, and a lot of the progress that we've made was a consequence of that generous gift. I want to thank you, Steve. 
(audience applauding)

Thanks so much, Dr. Maki.

So, so far you've heard an elegant distillation of the scope of the problem of antimicrobial resistance, and you've heard about some of the path-breaking research that Dr. Maki and his group have undertaken to help to prevent these infections. What you're going to hear about next is studies on the use of antimicrobials to optimize the therapy and the prevention of resistance to these lifesaving drugs.

Antimicrobial resistance, because of the emergence of the antimicrobial resistance, the use of antimicrobials has become increasingly complex. 

And, in fact, it's led to an entire new field of clinical service called an antimicrobial stewardship. Our next speaker is Dr. Alex Lepak. Alex was a graduate of this university, undergraduate, medical student, resident, and fellow. He trained under Dr. Craig and is not surprisingly an expert in the use of antibiotics and is one of the leaders of our antimicrobial stewardship team. And so he's going to talk to you today about studies ongoing here to optimize the use of antibiotics. 
(audience applauding)

Thank you, Dr. Andes, for that kind introduction. 

And I want to thank all of you for being here this evening. It's really a great honor and pleasure to present our work here in terms of antibiotic stewardship. So you heard a little bit from Dr. Maki about how antibiotics can be somewhat of a paradox, and that is they have this amazing ability to cure patients and save lives. In fact, if you look at life expectancy since the discovery of antibiotics, there's perhaps no modern medical technology that has made more impact on that, and life expectancy has doubled since the discovery of antibiotic agents. However, if we use them, we do place ourselves at risk of driving resistance in bacteria and therefore, we need to be very careful that we use them in the best possible manner.

Add to that, really, that, as Dr. Andes mentioned, modern medical healthcare is exceedingly complex. The number of patients that we see and the number of infections that we see now and patients at risk has really exponentially increased in the past two decades. And the complexity of these patients, and what I mean by that is the number of other diseases that they have and the treatments that they're on and what those treatments do to their immune system has really become dramatically complex. 

There are now over 100 antibiotic agents. There are more than 873, and the list is certainly growing, bacterial pathogens. And there's constant changes in what those bacteria are susceptible to and what they're resistant to. And so I think it's probably pretty clear to all of you that this is amazingly complex, and for the average physician it can be very difficult. And that's really where stewardship has come in, is we are there to help clinicians through all of these complexities to use antibiotics in the best way. So you might say, well, why don't we just take all the patients who may have an infection or may be at risk and just put them all on antibiotics? And there are a number of bad things that occur, unfortunately, when antibiotics are overused. There's increased antibiotic resistance. There's increased severity of disease, length of disease, medical complications, the healthcare costs go up, antibiotic adverse effects and toxicities are increased, and finally we see increased relapse of disease when antibiotics are overused. But perhaps most importantly is, if they're overused, it actually increases mortality.

So, what is antibiotic stewardship? There's kind of a textbook definition here for you on the left-hand side of the slide, and that is coordinated and multifaceted interventions designed to improve appropriate use of antibiotic agents by promoting the selection of the optimal agent, dose, route, and duration. What I tend to think of antibiotic stewardship is more represented on the right, and that is that we need to balance multiple goals. And one of those goals, and certainly perhaps the most important, is that we want to optimize care for a particular patient, but we have to keep in mind that there are other patients in the healthcare setting that are at risk of infection and we want to protect those people. We want to preserve antibiotics for future generations. This is a shared resource for all of us now and in the future. And we want to decrease antibiotic resistance.

So, the University of Wisconsin has really been a pioneer in stewardship. As Dr. Andes was mentioning, this is a very, very young field. 

The first guideline on how to perform stewardship was only published in 2007. Fifty years ago, our hospital placed pharmacists on rounds to help monitor and address antibiotic use to make sure that it was being used in the best possible fashion. And our antibiotic stewardship team here formally began in 2002. So, five years before even the first accepted guideline.

We have been recognized for this.

This is from the CDC website. We are one of 12 leading centers in antibiotic stewardship. This is an alphabetical list, so don't think that we're second to last of the 12. But, certainly, it is nice to be recognized as a leader in this area. So, there's a lot of things that we do as stewardship. 

There's probably more than a dozen core functions. I'll only have enough time to really touch on three of them that I think we do very well, and that is formulary restriction or prior approval program; the second is going to be dose optimization, which is how do we use the antibiotics better, how do we dose them better; and then, finally, the third is how do we real-time monitor a hospital of over 500 beds, how do we monitor the antibiotic use that's going on, and how do we streamline it? How do we make the antibiotic use in the hospital better?

So, I'll start with the first one: formulary restriction or prior approval. What we do is we place a select broad potent antibiotics. These are the antibiotics that are our last lines of defense. So these are the antibiotics that treat the very difficult to treat organisms and most importantly, drug resistant organisms. And these are the antibiotics we need to preserve and we need to be most careful about. So we place those on a restriction list, and providers need to call one of us in order to get approval to use that antibiotic. They need to discuss the case, after that discussion we'll either approve it or give them an alternative course to take. 

We have 12 antibiotics that are restricted at the University of Wisconsin, and we really were one of the first to implement a restriction policy, especially for multiple antibiotics. Ours started in 2003.

What does restriction get you? There's a lot of positive effects. I've picked, I think, the three most important here to point out. We know from experience here, and others have published, that it most importantly improves patient outcome. By restricting the antibiotic use, you actually improve patient outcome. You certainly decrease resource utilization, which probably makes sense. And, importantly, if you restrict antibiotics, you decrease drug resistance. And that can be true for even antibiotics that you're not restricting. 

So you can decrease the resistance across the board.

So, the second thing I want to talk about was dose optimization, which in the infectious disease field, we call that pharmacodynamics, which is how do we dose antibiotics in the best possible fashion to get the best outcome? As you heard from Dr. Maki, this is the birthplace of this field. Dr. Bill Craig is the father of pharmacodynamics, and he knew well before most other people recognized that we could do better. We could dose antibiotics better. And there was a way to do it better, and he set out on a scientific career to prove that. And his findings profoundly changed the way we prescribe every antibiotic today.

So, I need a minute to kind of set this up here to kind of pinpoint one of Dr. 

Craig's brilliant findings. What I'm going to show you here is four different ways that an antibiotic could be dosed. I'm sure all of you out there have had an antibiotic prescribed to you at at least one point in your life. And you may have gone to the pharmacy, picked up the antibiotic, and on the bottle there are instructions. And it says take a 100 milligrams twice a day. And you may think to yourself, boy, my son or daughter or wife or husband got an antibiotic a year ago, and that one was 500 milligrams three times a day. How do they know how much drug to give me, and how do they know how often I need to take it, and maybe most importantly, how do they know that that's the best way to do it? And that's really what Bill Craig set out to prove to all of us and did a miraculous job. So, on the Y axis here is the drug concentration in the body. So, as you go up the axis, there's more concentration of drug in the body. 

And on the X axis I'm showing you a one-day snapshot. A 24-hour period. And on this dashed line what's represented is the MIC, or minimum inhibitory concentration, for a particular organism. So we'll use a staph germ like Dr. Maki presented earlier. What the MIC is, is it's saying that at this concentration here you inhibit growth of the organism, and anything above that you would continue to inhibit growth of the organism, but anything below that level you wouldn't be able to inhibit the growth of the organism. So we've taken an antibiotic, here it's 800 milligrams, and we told the patient take the whole dose at once. And that's in the blue line, and you'll see that the drug concentrations rapidly rise in the body to a peak level, and then the body will eliminate it or metabolize it and the levels will fall off. Now, we've taken that same dose, 800 milligrams, but represented in the green line, and we've told that patient why don't you split this dose and take 400 milligrams now and take another 400 milligrams in 12 hours. And so you'll obviously get two peaks here but it'll be less because they're only taking 400 milligrams at a time. 

In the brown, we've gone to 200 milligrams, and now we've told the patient take it four times. So it's still the same 800-milligram dose. And finally, in the pink line, we've told the patient to take only a 100 milligrams but to take it every three hours, so eight doses. That's still 800 milligrams. So all of these patients taking these different regiments would all take the same amount of drug. And one thing that Bill noted was that if you look at these drug concentration curves for each of the different colors, they will actually lead to different times that the drug concentration exceeds this MIC level. So, for the blue line, you'll see that it's represented down here in blue as well, that the time that the drug concentration was over the MIC of the organism, or the minimum inhibitory concentration, is about one-third of the 24-hour period. But for the pink line, you'll probably appreciate there's a much longer period of time that this drug concentration is going to be above the MIC as you add up all of these periods of time. And that's represented on the bottom here with the pink line as well. So, just by changing the way you take the drug you could more than double the amount of time that the drug concentration was above the MIC. 

And Bill asked whether or not this was important, and he proved definitively that this was very important for a group of antibiotics called penicillins or cephalosporins. And here, on the Y axis, is the bacterial burden. Each of these blue dots is a group of mice that he studied that were infected, and this dashed line now is the infectious burden at the start of therapy. So when your time above MIC for penicillins was 30% or less, you can see organism continued to grow despite the antibiotic presence. And when you got about 40% or more above the MIC, you got up to maximal killing.

And so this led to a hypothesis that was driven then clinically. We took this data to the bedside and said, well, if time above MIC is really the critical factor, then maybe we should try to improve that to patients. And the hypothesis was that let's give beta-lactam antibiotics, penicillin, penicillin related compounds, but instead of giving it over a very short infusion time, which is how most IV antibiotics are given, they're administered over 15 or 30 minutes, if we slow down the infusion and make the infusion last three or four hours, we can maximize the amount of time that the drug concentration will be above the MIC for that particular organism. And we studied that here and looked at it in patients and it was overwhelmingly successful. In the blue lines is the conventional dosing or the dosing that would go over only 15 or 30 minutes, and in the red is prolonged infusion. 

This is dosing over three or four hours. You can see ventilator days, far less. ICU length of stay, much less. Hospital length of stay, much lower. And most importantly, mortality, much less when we actually maximized the time above MIC by giving it by prolonged infusion.

The last thing I will hit on is how do we, in real-time, monitor antibiotic use at the hospital? And we do this through our electronic medical records system. We built here a system of flagging charts. So these are computer rules that are written by us to identify patients who may need antibiotic stewardship intervention to optimize their care. One example of one of those rules is prolonged use, so more than 72 hours, of multiple broad spectrum drugs. 

It's very common for a patient in the initial stages of their hospitalization to need more than one antibiotic, but after 72 hours, that's very uncommon. Most of the time, these patients can be put on a very targeted type of antibiotic. And so, through these flags, we look at the charts. It generates a lot of charts to review. More than a hundred charts per day.

And in terms of when we went live with this system, we went live in 2011, and the intervention is that we generate a note to clinicians in the EMR system that says that we've reviewed your patient and we feel that certain changes will benefit your patient from an antibiotic perspective. What I think is important to note is this BPA, best practice alert, that we file, this stewardship system that we made in our EMR has now been adopted by our vendor and is used all throughout the world. So, this is what a physician would see when they logged into their chart. They'd get pop-up, bright pop-up that says that we have looked at the chart and left recommendations for them. And they would click on that, and they might see a note similar to the following. 

In this case, this is like the example that I mentioned on the previous slide. We're saying your patient has completed 72 hours of broad spectrum therapy, in this case it was three different antibiotics, and that the results are back and there's no difficult to treat bacteria, there's no drug resistant bacteria, and we feel that the patient could be very appropriately narrowed to a single agent. So, how successful is this, you might ask, right? It still takes them reading it and then deciding whether or not they think our ideas are good ideas. So, in 2013, we generated 32,000 stewardship alerts on inpatients. And from those 32,000 reviews, we made 710 BPAs within our EMR system, and 75% of those are accepted. So, overwhelmingly successful. Another 15% are accepted with some sort of modification made to our recommendation, and only 10% or so are rejected. And this doesn't even scratch the surface of a multitude of other interventions that we do such as dose adjustments or dose optimization, very similar to what I was discussing in the second example based on Dr. Craig's research. 

And what has this done here for us? We have realized a 30% decrease in antibiotic use since 2010.

I will leave you with this slide. This is from the University of Pennsylvania. We have similar results here. I like this slide because it very succinctly, I think, shows you what antibiotic stewardship program can really do for an institution, can do for a hospital. So, here they allowed a group of patients to be treated as however the physicians wanted to treat them. So that's called usual practice. And then another group of patients they enrolled into an antibiotic stewardship program where there was an infectious disease physician and pharmacist overlooking their chart and kind of helped directing the care. And you'll see that the use of antibiotics, makes sense, went way up. 

It was only about 30% of the use was appropriate in the usual practice group and over 90% when an antibiotic stewardship program was involved. But importantly is the cure. Cure was only about 50% in the usual practice and over 90% when an antibiotic stewardship program was involved. And failure of antibiotic therapy was far lower in the antibiotic stewardship program. And just in terms of cost savings, they calculated that the antibiotic stewardship program saved their hospital more than $4.25 million. So, the stewardship team is very large. There's a lot of work. There's a lot of people that deserve recognition. You will note that all four of the speakers here this evening are intimately involved in stewardship.

Thank you. 

(audience applauding)
- So, you've heard about approaches to prevent these infections. You've heard how to optimally use these antibiotics to both prevent the emergence of resistance and to optimally treat the resistance infections. Next you're going to hear about another superbug, but in addition to hearing about this superbug, you're going to hear about a group of good bacteria. Bacteria that are referred to as the microbiome. These are bacteria that live normally with us, and we actually need them. You might not know that, in fact, the number of bacterial cells in your body outnumber the human cells by more than a factor of 10. So you're going to hear about this from Dr. Nasia Safdar. Dr. 

Safdar was trained by Dr. Maki. She is an expert in the area of infection control and hospital epidemiology. She's the head epidemiologist for the UW. She also is a leader of research at the Veterans Hospital and in the Department of Medicine. So, Dr. Safdar, can you wheel up here for us. 
(audience applauding)
- It's a pleasure to be here. And today we're going to be talking about one of the most dire consequences that inappropriate antibiotic use can have, and that's the emergence of Clostridium difficile infection or Clostridium difficile associated diarrhea or C. 

diff, as it's more commonly known.

So a few decades ago, C. difficile was considered to be really a nuisance pathogen but really nothing to write home about. People received the anti-infectives. They got C. diff, it was readily treatable, and they did just fine. But that picture has completely changed, and the face of the new C. diff is a pathogen where rates in the US and globally have doubled in the last decade. We get over three million cases per year in this country alone. And the unadjusted fatality rate has increased from about 1% to almost 3%, which, if you translate that to the number of people that are dying from this infection, is much, much higher than it used to be. 

Most people that will get C. diff have traditionally been older, immunocompromised, or with other comorbid illnesses, but even that's changing now such that it's the younger people in the community that we're now starting to see C. diff in at a cost to the health system of over $3 billion. C. difficile is very aptly named because it was originally called difficile because it was difficult to grow in culture, and people didn't know quite what to make of it until they were able to streamline their techniques and get it to grow. But it's also exceedingly difficult to treat, as I'll show you in just a minute. Now, sometimes people ask me, well, it's just diarrhea. So I've had C. diff, I'll recover from it, is it really such a big deal? And there's limited literature on it, but a qualitative study that we did at this institution just recently of 17 patients who were coming to the infectious disease clinic with C. 

diff, and when asked that question, how has C. diff impacted your quality of life, well it's resulted in a complete reconfiguration of their entire social structure such that many of them don't get to see their grandkids anymore or their children. Many of them say, "I just stay home now "because I never know when something will happen "that will require me to immediately go to a restroom." So, C. difficile is not just diarrhea. It's a major infection that people suffer from for sometimes months at a time. Now, the initial episode is certainly not pleasant, and this is probably not a good time to talk about diarrhea right around dinnertime either. But, so even if you recover from the first episode, what happens to subsequent episodes? About 15% to 20% of patients will have a relapse from C. diff, in all likelihood because the factors that prompted them to get the infection in the first place still exist, and so they get a second episode. 

Those that get a second episode are much more likely to get a third episode and so on until you get this vicious cycle where you have C. diff more often than you don't.

Treatment failure is also an emerging problem. It used to be, as early as 10 years ago, Metronidazole, or Flagyl some of you may have heard, was considered the first line treatment for C. difficile. And people responded well to it. About 90% success rate. Now the success rate to Metronidazole alone has really come down to about 40% to 50%. And there was an editorial recently where somebody suggested that Metronidazole is the drug that's now only good enough for your mother-in-law, but you wouldn't want to give it to your mother if they had C. diff. 

(audience laughing)
 That joke never fails, I can tell you that. No matter what the audience. So, what we're left with is then there's no universal treatment algorithm for recurrent C. diff, and that's where the need for research comes in so urgently. Now, what is it about C. difficile that makes it so difficult to get rid of and so difficult to cure? Well, this slide shows you what the life cycle is of C. diff in the human body and in the environment. So, starting from the left side of the slide, what you see is it's a fecal/oral transmission. 

So somehow the C. difficile, which can exist in spore form in the environment, in the community, and in healthcare institutions, has to be ingested so that it can get into your stomach. Normally, your stomach acid would be able to get rid of the vegetative forms of C. difficile but not the spore forms. The spore is extraordinarily resistant to just about anything you can think of, and that's how it has evolved over millions of years to protect itself and to keep it going. So in the intestine then it germinates, and when it germinates two things can happen. People can either become colonized with C. diff, meaning that they will have it in their intestine but not necessarily get symptoms immediately, or they get diarrhea from it. And when they do, the spores are then shed into the environment where they can then be found in the food, water, and healthcare institutions. Infants, surprisingly, over 90% of them when they are born, within the first year of life, will be carriers of C. 

difficile. They don't often get sick from them, but they're certainly more than capable of transmitting it to their moms and their grandparents and anyone else that's looking after them.

So what is required for C. difficile to happen? I think in order to understand what makes us vulnerable, it's important to recognize that our biggest and best ally are the healthy gut bacteria that we carry within us. And it's pretty clear looking at all the things that the healthy gut bacteria can do for health that it's not the humans that are ruling the Earth. If we can keep a microbiome or the normal bacteria in balance, we are well positioned to resist invasion by most pathogens. So, for example, if you or I, preferably you, were to drink a slurry of C. difficile, nothing would happen. But if I were to give you one dose of an antibiotic and then have you drink that slurry, about 20% to 50% of you would get C. 

difficile infection. So another good reason to avoid anti-infectives unless you absolutely have to have them. So the pathogenesis starts from hospitalization after which there's antibiotics given for whatever reason, for example, and then because there's C. diff in the environment, people will acquire it, and then some people will get colonized and some will get diarrhea. And what determines who will get what is entirely dependent upon two things then: the stability of your normal gut microbiota or normal gut bacteria and how good your immune system is. Are you able to resist C. diff, or do you succumb to it? Now the clinical spectrum can range. So, it's true that some people will get mild disease and will just manifest itself in the form of antibiotic associated diarrhea, but many people will get severe colitis or inflammation of the intestine but will not have what are called pseudomembranes. Pseudomembrane essentially just means that the intestine lining is being sloughed off because of as a result of the toxins that C. 

difficile is producing. If you see pseudomembranes, and that's generally see on endoscopy, that's a sign of severe infection. And finally, a small but significant minority of people will get fulminant colitis and will require ICU care and removal of their colon to treat the condition. So, why do we get recurrent C. diff? Well, one is the impaired host response as I alluded to earlier, and the other is the alteration of the intestinal microbiome. And if you had to pick one thing, what is the one thing that can alter your intestinal bacteria? Well it's the antibiotics that you get for treatment of infection. They not only kill off the organism that's causing your infection, but also all the baseline bacteria that were there, with the exception of C. diff. 

Many of them will not kill C. diff, so C. diff will overgrow and then cause infection. So, what happens with recurrent C. difficile? I think slide is very instructive because these are relatively new findings that I think may set the stage for future therapeutic options. So if you look at the healthy gut bacteria, how do we know that it's healthy? Well one marker of health is diversity. The more different types of phylotypes or the more different kinds of bacteria in the intestine, the more healthy the bacteria are considered to be. And here on the Y axis, you see that there is the increasing number of phylotypes. 

So that's a sign of a healthy gut, microbiome is what I'll call it, also synonymous with healthy gut bacteria. So for people that don't have C. difficile, which is the control group, you can see that the gut bacteria is fairly diverse and they do fine and it's very healthy. Now, with the initial episodes, which are the red lines here, there's some decrease in diversity, but it's not very marked. But look what happens to recurrent C. diff. They hardly have anything in their intestine that they should have in terms of the healthy gut bacteria. And this is the effect that then I think perpetuates what people get recurrence after recurrence. If you look at it differently, you can see with the colors here, these just represent the main types of bacteria that we expect to see. So on the left side are all the people that either have no illness or that have had a first episode of C. 

difficile. But look at the difference in colors with people that have recurrent C. difficile. This stuff in purple, which is the Proteobacteria, has no business being there in the normal gut microbiome. But when you are left with voids there because of C. diff, that's what happens to the gut microbiome that makes you predisposed to C. diff in the future as well. So in order to recover, we have to bring back this diversity. And how do we bring back diversity? Well, one really outside the box thinking approach is to instill a sample of stool from a healthy donor into the intestine of somebody that has C. 

difficile. You can't get more, in trying to recover the microbiome, than putting an entire community of bacteria in its environment in the stool. Or as the French call it. 
(audience laughing)
 Now, this is not a new concept. It's new in the sense that it's really taken off since we've discovered that C. difficile is so hard to treat. When options are limited, we look to whatever is available. But many years ago there were several case theories of people that reported instilling normal feces, and thereby curing C. difficile. 

These were met with I think, some skepticism at the time and are thinking that well, that may have been the case then but now we have other options. Well now we're back to the time when we have no other options. And so fecal microbiota transplant is something that we have embraced as a treatment for C. difficile for the plain and simple reason that it works. Our program for fecal microbiota transplant at UW has been going on since 2013. We have transplanted about between 48 to 50 patients with C. difficile, many of whom have had more than two recurrences and many of whom were very immunocompromised. And our success rate mirrors what's being seen around the nation, that 95% of people will recover, if not with one, then certainly with two fecal transplants. What's also interesting is that unlike the conventional medications like Vancomycin and Metronidazole, the response rate with FMT, or fecal microbiota transplant, is very rapid. Within two days of having received it, they'll say they're back to their baseline stool status, which is not something that they would have experienced with any of the other conventional anti-infectives. 

So the rationale is obvious for FMT, that you want to avoid prolonged repeated courses of antibiotics and you want to reestablish your normal diversity of the intestinal microbiome. The devil, however, is in the details. And you will find that there are many, many protocols nationwide. So every institution you talk to will have their own specifics about who is the best donor that should be used to provide stool. Some people have suggested medical students might be one group that perhaps could be those donors. There are many exclusions. You want your donor to be the healthiest individual possible because, as they are giving your their bacteria in the stool, they're also potentially giving you other things because we know that the gut bacteria modulates more than just infection. It also has a role to play with obesity, with heart disease, with cancer even some studies suggest. So the donor has to be chosen carefully. And then the donor has to be tested vigorously to make sure that we are not unwittingly transmitting another infection while we are treating their C. 

diff. And we have a very rigorous protocol for that. Now surprisingly, when we first started to do it, people had legitimately, I think, raised the question of do we think that patients will be accepting of this treatment and whether they will even want to undergo it, given that it's obviously not very pleasant. And this is one study that looked at it. They gave people hypothetical cases, and they said here's a new treatment that can provide a cure rate of about 90%, would you be willing to have it? And 80% of the people said yes, we will go with that treatment. They didn't know that it was fecal microbiota transplant. That was being talked about. But even when it was disclosed to them, the numbers didn't change, which suggests that once you've had a couple of episodes of C. difficile and there's no other options, you'd be willing to undergo this treatment because you know that it works. 

Physicians are a little bit more conservative, and the guideline suggests that you would probably only want to do an FMT treatment after about two or three episodes of C. difficile just because not everyone who has a first episode will get a recurrence, so you might want to give them a chance to see if they do just fine, then they don't need anything. If they get a second episode, then it's time to entertain the possibility of FMT. But what is the evidence behind FMT? We've got case theories, we've got case reports, and we've certainly got a lot of anecdotes. You may have read in the paper people describing how they're doing it at home, and it's working really well for them. But for the first time a couple years ago, the one and only randomized control trial of FMT was published in the premiere journal the New England Journal of Medicine. And what they found was this was tool that was administered through a nasal gastric tube, or an NG tube, and what they found was that if you compare the best available medication at the time, which was Vancomycin, it only had a success rate of 30%. And if you look at the success rate with infusion of donor feces, it was about 94%. So that made it pretty clear that this treatment option was coming here to stay. 

And then in terms of mechanism, one of the questions you would want to ask yourself is, well has the diversity of my gut microbiome really been restored by this treatment? And that's another thing that these investigators showed. This is what the gut microbiome looks like in terms of diversity of the donor. This is what the recipient looks like before they've had the transplant, so very low diversity. And then after the transplant, it mirrors that of the donor. So it does seem to take in the large proportions of patients that get this treatment that the microbiome becomes more diverse. And seen another way, this is what happens. Here is what the donor looks like. Very healthy microbiome. Here's what the pre-FMT recipient looks like. 

All the reds suggest that these are organisms that shouldn't be there in the healthy gut microbiome. And right after the FMT, it looks just like the donor. That's pretty compelling. You can't make this stuff up. It's really very exciting. So 92% of people experienced resolution. Really no adverse consequences, and the ones that did occur all occurred from other underlying conditions rather than from C. difficile with the exception of one. But again, there's a variety of ways in which FMT can be administered. You can do it via colonoscopy, via nasal gastric tube, via an enema. 

At our institution we have chosen to use the enema because it produces the same results with very low risk to the patient as opposed to the sedation required with a colonoscopy, for example. Some of these other things are more details about how to administer it. So I put this only up here to suggest that this is probably not something you want to try at home. If it's something you need, you come to the Infectious Disease Clinic, and we'll help you get it sorted out. Now, patients always ask me, "I've had FMT and I'm doing well now, "but what's going to happen to me long-term? "Am I going to struggle with this again "in the next three months?" So there's a few studies that have now started to look at the long-term outcomes of FMT, and it turns out that it works pretty well and patients do quite well for months after the procedure with one exception. If you get another antibiotic for some other reason during that time, then you might land yourself back at square one and need another FMT. So, another reason to then avoid anti-infectives after an FMT as well. Many people would say that if that happens, they would be willing to undergo another FMT for recurrence.

So the drawbacks are fairly obvious. It's aesthetically unpleasing. There have been some issues with reimbursement for insurance. Although, Medicare now covers it and most insurance companies are beginning to cover it as well. We try to be cautious with the potential transmission of pathogens by testing people rigorously. The pros are it's efficacy, which is unlike anything we've seen, and the fact that it is relatively inexpensive. When you look at the cost of a 10-day course of anti-infectives, those turn out to be more than what an FMT costs. This slide I put up just to give an idea of the tenacity of C. difficile. In the '70s, it seems hard to believe now that we didn't always know that C. 

difficile was the cause of antibiotic associated diarrhea, but in the '70s it wasn't known. People were getting something called Clindamycin, which was an antibiotic, and they were getting diarrhea but the link between the two hadn't yet been made. So there was a 13-year-old patient in Michigan, and her physician collected a stool sample and sent it to the CDC for further testing. The stool sample was misplaced, and they didn't know where it was. 21 years later, they found it hidden in some dark place in the CDC. They were still able to culture it. It was still producing toxin. So you can run, but you can't hide. 
(audience laughing)
 Now, if you're looking for opportunities of what to do in your spare time... 

(audience laughing)
 There are universal donors that we need to keep our program going. I don't know that you would want it to be advertised as heavily as this person did. But maybe something to be proud of, your really excellent gut microbiome. Now, if you think about the downsides of the stool transplant, it's really the fact that we don't want to transmit anything that's as yet unknown. So people have tried to see can we take the core group of 30-50 bacteria that are in the intestine and grow them up and have a population of bacteria that we can just inject into the intestine rather than doing the whole stool approach. And this therapy called RePOOPulate... Was not surprisingly developed in Canada. I'm just kidding, but it is Canadian. So they have this robo-gut, which will produce or provide an environment for these organisms to grow. 

Unfortunately, it doesn't look like it's very easy to scale it up. So even though they were able to do it for a few patients, it wasn't able to be in a place where it could be commercialized. So then the next question is, "Well, how else can I administer FMT?" An enema is not pleasant. Colonoscopy is not pleasant. Could I administer it in the form of a pill? That's all very well unless the capsule opens while you're trying to take it. 
(audience laughing)
 And there's a lot of them. At least the current available literature suggests that it's not commercially available or viable, but I think there's a lot of work being done here where we can eventually get to a point where you can securely package it so that there are no accidents and the number of capsules can be brought down. 

I think down the road this is probably where the field is likely to move. So the future direction are to use a universal donor which is very rigorously tested, potentially to use an artificial stool synthetic alternative, and then think about route of administration and safety. 
(audience laughing)
 While that happens, we do the best we can. Thank you very much. 
(audience applauding)

Thanks very much, Dr. Safdar. You forgot to say you'll be taking phone numbers afterwards for potential donors, correct? So, you've heard about work from three innovative groups, work that has already reached the bench, from the bench to the bedside. 

Things that are already helping patients. What I'm going to talk to you about for the final talk is work that we're excited about but work that's not yet reached the patient, and that is a team science approach from investigators across this campus to discover new antibiotics and to develop those antibiotics. Dr. Maki already elegantly demonstrated to you the importance of these miracle drugs. The impact that they've had on our ability to save lives for patients that acquire these infections. And in fact, this is arguably the most effective pharmaceutical drug class that has ever been developed.

But not only has this drug class impacted our ability to treat infections, but they've really revolutionized the practice of medicine because many areas of medicine result in a vulnerable patient, a patient that's vulnerable to infections. And prior to the antibiotic area, those patients would die from their infections. But because of antibiotics, we're now able to successfully perform complicated surgery, including organ transplantation, effectively treat cancers, and get patients through that immunosuppressed period, take care of premature babies, and save patients in the critical care setting that develop, unfortunately, nosocomial or hospital acquired infections. But this pharmaceutical class is unique in another way in that they're the only drug class that I'm aware of that predictably lose effectiveness over time. 

And what this cartoon shows you is a timeline, and at the top of this timeline is the date that a variety of antibiotics came into clinical use. And what you see on the bottom is the time after the introduction of that antibiotic that that antibiotic lost effectiveness or began to lose effectiveness. So, here is, you heard about, the first natural product antibiotic, penicillin, introduced early in the 1940s. And it wasn't until only a little after 1945 that clinical resistance was described. Now move forward a few decades to the very last of the antibiotics that has been discovered and developed, and that's Daptomycin, and that time has shrunk. Now, this time doesn't always shrink, and in the average lifespan or useful lifespan of an antibiotic is probably less than 10 years.

So, early on this wasn't such a big deal, as this graph shows you. So what this graph shows you is a timeline from when just after penicillin was discovered until almost 2000. And on the Y axis, you see the number of new antibiotic discoveries per year. So, when we started to see antibiotic resistance, up until the late 1970s that wasn't such a big deal because there was the new antibiotic that was going to be discovered tomorrow. 

But you can see here, as Dr. Maki showed you, a precipitous decline in that curve. And in fact, that last new antibiotic I mentioned, it was Daptomycin, and that was discovered in 1987. So that's the last new novel antibiotic drug class that has been discovered and made it to market. And there are a number of reasons for this precipitous decline. There are fiscal reasons, and there are scientific reasons. So fiscally, the large pharma, the large pharmaceutical industry has largely abandoned antimicrobial drug discovery because the return on investment is much less than research in other therapeutic areas. And I'm going to talk to you about some of the scientific reasons for this precipitous decline. And what I'm going to talk to you about is research as I mentioned from a team of scientists across campus, and this is a diverse group of people that were brought together intentionally by campus through mechanisms such as the Perlman Symposium in immunology. Scientists brought together with a common goal but from different areas. 

And so this group of scientists includes everybody from an evolutionary biologist to microbiologists, pharmacologists, and chemists. And obviously, our goal was to find the next antibiotic, but not just to find the next antibiotic, to find a sustainable antimicrobial discovery and development platform. And we had three hypotheses that were underlying the research program that we've put forth. And the first is that natural products will be the ultimate source of those new antibiotics, and I'll get to why we hypothesized that in a minute. And the second is that we thought we had found a new source to find these for these antibiotics, and we thought we had come up with two or three new ways to try and discover the antibiotics from those antibiotic sources. And I'll tell you about that in a bit. So again, why do we think natural products are going to be the next source? And that's pretty simple and that's history and that is because 75% of all of the antibiotics that have been discovered and brought to clinic to date are actually natural products. So what is a natural product? A natural product is a chemical that's made by either a plant, an animal, or a microbe. 

That microbe could be a bacteria or a fungus. And why are these chemicals different than other chemicals that we might synthesize or make? They're different because they have an evolutionary history, okay? So they've been selected to produce this chemical, in this case an antibiotic.

Dr. Maki introduced the first natural product antibiotic that was serendipitously discovered by Alexander Fleming, but he also mentioned that he had trouble beyond that initial discovery. He couldn't actually purify or make enough of it reliably to get it into therapeutics into patients. What you might not know is the role that scientists on this campus played in the production of enough penicillin to treat patients. So actually, right around the time of World War II, a group of scientists made key discoveries in this area. One scientist, Ken Raper, actually discovered the fungus that was the optimal producer of penicillin and actually, he found this fungus growing on a watermelon in Peoria, Illinois.

An additional group of scientists genetically modified that fungus such that it produced even more penicillin. And then yet another group of scientists developed fermentation methods that allowed massive production of penicillin. And it was the work of these groups that led this World War II to be the first war that more soldiers actually died from bullets than from infections.

So, I think it's instructive to look back historically, where have most of these antibiotics come from? Where did industry find all of those natural product antibiotics? They found them in the soil. They found them in a non-biased way by looking at microbes in the soil for antibiotic production. And that worked, as I showed you, for a while, but what they found over time is they started to find the same antibiotics again and again and again. So they'd go to another part of the world and scoop up the soil, isolate the microbes, see what antibiotics were produced, and 99.5%-99.9% of the time, they would find the same antibiotic. In fact, that last antibiotic I told you about, Daptomycin, I'm told that it took them screening over a million different microbes to find that new antibiotic. 

So the common sentiment from industry was that this natural product well is dry. And scientifically, this is why they abandoned antibiotic discovery in the natural product sense. But we question that sentiment for two reasons. First is it's suggested that less than 1% of the microbes on Earth have been assessed for antibiotic production. Secondly, when we look at a subset of the bacteria that haven't been assessed for antibiotic production, we find a genetic code that suggests antibiotic production potential. So what this complicated figure shows you is first a bacterial family tree as you move around this circle. And each of the colored bars coming off of this circle represent genes that have a signature that suggests antibiotic production. And the height of those bars represent the antibiotic potential. So we think that there's a lot of untapped natural product antibiotic sources out there in the environment. The question is how to find them. 

Well, that brings us to our group. And the discovery of an evolutionary biologist, Professor Cameron Currie. So Cameron studies symbioses. So symbioses are studies between living beings and an environment, okay? And so he studies the evolution of those organisms living together, and he's interested in ants. Actually, leafcutter ants. And what he found was in these large ant colonies, he found actually four living beings. So he found the animal, which is the ant. He found a fungus that these ants farm. They don't eat the leaves. 

I kind of thought they did initially, but actually, they feed the leaves to their fungus. So they're farmers. He found a pathogen in the environment, a pathogen that would kill their fungus farm, and then the ant colony would die. And he found a fourth organism, and that fourth organism he found living on this ant. Actually, in these crypts on these ants. And he found that that was a bacteria, and that that bacteria was producing chemicals. And some of those chemicals actually were effective in killing off the pathogen so the bad fungus or the bad bacteria in that environment. So he found a symbiotic bacteria that was making antibiotics to protect the ant in that environment.

And so that's all well and good, but he found out that this had happened evolutionary. In fact, I've showed this on growing on the breastplate of this ant, but actually, the ant has evolved to accommodate this bacteria. 

In fact, there are special crypts just for this bacteria to grow, and there are actually glands that have evolved to actually feed that bacteria. So this is something that he's shown that has evolved over tens of millions of years. And that's kind of a cute discovery, right? But he went on to show that this isn't unique. This is not rare at all. In fact, in every insect species that we look in, whether it's a wasp or a termite or a honeybee or a pine beetle, he finds these symbiotic relationships. He finds symbiotic bacteria that are producing chemicals. And because, again, these microbes, the animal, the insect and these microbes have evolved to live together, the likelihood that they're producing chemicals that are biologically important and frankly, safe for the animal in that environment is very, very high. So I told you again, the last time that we found a new antibiotic, Daptomycin, it took screening over a million microbes. So, in the first 200 symbiotic strains that were isolated in his laboratory, he's already found 30 novel antibiotics. 

A hit rate, if you do the math, that's greater than a hundredfold greater than history. Now, we're pretty encouraged because it's estimated that there are more than 10 million insect species on the planet. So lots of new antibiotics to find. And this isn't something that's unique to insects. We actually have found similar relationships in the ocean. And so Dr. Bugni, who's a professor in the pharmacy school, studies these symbiotic relationships in marine animals, particularly sponges and ascidians, and he's found a similar thing. So of the first 100 bacteria that he isolated, we find 35 new antibiotics. Again, a hit rate even better than Dr. Currie's. 

So we found a new place, how are we looking? Well first again, how did industry look? So again, I mentioned they would go and they would collect soil, they'd put that soil on different auger, they'd isolate different bacteria, and then they grow that bacteria up, and they would collect the culture supernatant, and then they would see if that culture supernatant would inhibit the growth of bacteria. Much like Dr. Maki showed you that Dr. Fleming had discovered, right? That fungus that was killing the staph around that fungus, right? So that's how they looked. But again, that's led to a lot of rediscovery. And I'm going to tell you about two methods that we're using that are different from that screening method. 

The first is what I call the needle in a haystack method. And this is work from Dr. Bugni's group, and he performs chemical analysis of the culture supernatant from these microbes that we find in the symbiotic bacteria. And he has an analysis method that he can compare to the chemical library of every chemical that's been discovered and reported on Earth. And he can very, very rapidly and accurately find that needle in a haystack. So what we're looking for here is not penicillin that's probably in here, not Azithromycin that's probably in here, but that new chemical entity that we hope will be an antibiotic producing microbe. Secondly, I've already introduced you to the genetic potential of these organisms. But what we're doing is taking advantage of that. Again, the genetic, genes that produce antibiotics have a particular signature, and we, with modern methods, can very rapidly sequence the entire genome of these organisms and we can identify the genetic potential of microbes that we find in these symbiotic environments and select those for screening. And again, both of these methods so far are resulting in an extremely high hit rate. 

We've only been working for a little bit over a year. And again, we had a number of milestones that we hope to achieve. The one I think we're most proud of and excited about is this number, and that's the number of new compounds that we've found that have antimicrobial activity against the drug resistant bacteria that you've heard about here tonight. We've moved a number of them into animal studies, and we hope in the coming 12 to 24 months to not only find additional antibiotics, but to take these antibiotics to the patient's bedside.

So again, we found what we think is a rich, untapped source of new antibiotics taking advantage of evolution, and we've initiated a number of novel ways to look for those antibiotics. And again, we have, with the resources on this campus, really a mini pharmaceutical company in-house. We have the ability to not only test for the activity of these antibiotics, we have the ability to study their efficacy in animals, move them to the benchside, discern their mechanism of action, and we hope in the end, identify a number of new drug leads. So with that, we'll conclude tonight's session and hope that we've shown you that antibiotic resistance is an important problem. In fact, it's a growing crisis. But that it's not the end of the world. 

That there are approaches to avert this crisis, and these include methods to try and prevent the acquisition of these resistant organisms by preventing infection in the hospital. To use antibiotics optimally.

And to take advantage and restore the normal human microbiome, again, to prevent not only the emergence of C. difficile but in studies that Dr. Safdar has done as well. Not only does altering the microbiome impact C. difficile, it also impacts the acquisition of other drug resistant organisms as well. And lastly, we're really excited about what we think is going to be the next generation of new antibiotics, and we hope to have those at the bedside very soon. So with that, I'll thank you so much for your attention, and I think we're going to be taking questions here shortly. 
(audience applauding)