"Antibiotic Stewardship: Bad Bugs, No Drugs"

Can you all hear me okay? Okay, I've got two microphones. I feel like I'm giving a press conference or something. Uh, just, uh, Dr. Rome, thank you for that very nice introduction. It's a bit of trivia, the last time UCLA went to a bowl game with a losing record was 1982, I believe, and the quarterback at that time was someone named New Heisel, also. So, anyway, couple disclosures. I do own some common stock in Optima and Merck. I will not be discussing either of those companies. I have a couple research grants. I will also not be discussing those. I have taken antibiotics and I've had infections.

So, I want to take you back to what we consider the dark ages of medicine, and that's December of 1942. A four-year-old girl, who had been in excellent health, suddenly developed severe facial cellulitis. That's a skin infection of the face. Now, this little girl was actually in Rochester, Minnesota, home of the Mayo Clinic, and her father was visiting from Venezuela, doing his neurology residency. And the father and mother went up to the twin cities and left the four-year-old girl in the care of the nanny, who was also from Venezuela and did not speak any English. She actually was running with a pencil, one of those things parents tell their kids not to do, and she tripped, and the pencil got stabbed up under her jaw. And back in those days, there was no 9-1-1. There was no real good emergency care. And the non-English speaking nanny really didn't know what to do. And over a couple of days, she got a high fever to 104. She couldn't sleep because her face and neck became so swollen, and she could not swallow her own saliva. When she began gasping for breath, finally, she was brought to the local emergency department. And I apologize for those of you who are eating lunch. This is her now. This is a surgical drain. This is so they had, they used a scalpel and opened that up to drain and put a drain in. And the doctors who saw her said that she was moribund and that she would be dead within two days.

Well, an infectious disease doctor named Wally Harrell is the first doctor in the United States to have access to penicillin through his connections with the War Production Board. So he gave this little girl penicillin, and she was actually the first person in the United States ever to receive penicillin. And that's 14 days later, totally fine for 65 years. Okay, she made a complete and total recovery. This is a brilliant book I would recommend reading called "Notes of a Medicine Watcher" by Lewis Thomas. 1983, and he talks about this early days of antibiotics. And he says, for most of the infectious diseases on the wards of Boston City Hospital in 1937, there was nothing that could be done beyond bed rest and good nursing care. If you think about it, why do you come into a hospital with an infection in 1937? You basically, the nurses take good care of you, they change your bedpan, they give you soup to eat, but really, there was nothing else that they could do for you.

Then came the explosive news of sulfanilamide and the start of the real revolution in medicine. I remember with astonishment when the first cases of pneumococcal and streptococcal septicemia were treated in Boston in 1937. The phenomenon was almost beyond belief. Here were more abundant patients who would surely have died without treatment, improving within a matter of hours and feeling entirely well within the next day. We became convinced overnight that nothing lay beyond reach for the future. Medicine was off and running. 1937. Just, you can feel the optimism that comes across there. They were on the cusp of this revolution in medicine that literally these patients who were dying overnight were being cured. It's an amazing thing to think about.

Thanks to penicillin. He will come home. This is a famous advertisement from Life magazine. "From ordinary mold, the greatest healing agent of this war." And there are some historians who feel that the reason that the Allies won World War II was because we had access to penicillin.

This slide shows the power of antibiotics. We see here on the left, some very common diseases: pneumonia, endocarditis, which is an infection of heart valves, meningitis. And then the antibiotic pre-antibiotic, rather, death rate. If you had infection of a heart valve back in 1937, you died 100% of the time. Very famous people have died of endocarditis. Gustav Mahler, Alois Alzheimer, who discovered Alzheimer's disease, died of endocarditis. Death rate in the post-antibiotic era, from 100% to 25-75% change. Pneumonia used to kill a third of people, one out of three people who got pneumonia used to die. Now it's one out of ten. Even cellulitis, which is a simple skin infection, probably a number of you in this room may have even had cellulitis. It used to kill 11% of people. I've never seen someone die of cellulitis. It used to kill one out of ten people. Now it's less than 0.5%. Incredible the power of antibiotics. And by comparison, treating an acute MI, a myocardial infarction, heart attack, with aspirin decreases the death rate by 3%.

But this is where we are now. This is the Los Angeles Times. This was published in March. "Drug-resistant bacterium hit Southland health care facilities. Researchers find 356 cases of carbapenem-resistant Klebsiella pneumoniae, mostly among elderly." It's a relative of E. coli, resistant to most antibiotics except colistin, a drug so powerful it can cause kidney damage. Studies in the US and Israel have shown about 40% of infected patients die. So this is a strain of bacteria we are seeing in our hospitals. Fortunately, most of the cases at UCLA are patients who have brought it from elsewhere, especially long-term care facilities. But we have seen a number of cases here. This is a bacteria that is literally resistant to every single antibiotic we have except for one, colistin, which was an antibiotic discovered in the '60s and abandoned because it was considered so highly toxic. So people stopped using it for 40 years until the last decade when we've used more of it than we ever have in the last four decades.

Okay, so this is where we are now. We're at a double crisis. That we have antibiotic-resistant bacteria like this one, and we don't have antibiotics to treat them.

This slide shows the discovery of new classes of antibiotics. And in the '40s and '50s and '60s, it was amazing. It was a revolution in medicine. We had all these new classes of antibiotics. And then in the 2000s, we had two new classes that were treating what we call gram-positive bacteria. That's stuff like Staph and Strep. But gram-negatives, like that nasty Klebsiella I just showed you, we don't have any new classes to treat those bacteria for four decades. It's been 40 years since fluoroquinolones were discovered. So John Bartlett, who's a very famous infectious disease doctor, says, "For gram-positives, that's your Staph, we need better drugs. For gram-negatives, like E. coli and Klebsiella, we need any drugs."

Meanwhile, antibiotic resistance is skyrocketing. This is data from the CDC. A lot of you have probably heard of Methicillin-Resistant Staphylococcus Aureus, MRSA, or MRSA. Okay, this is just since 1980. We're up to around 60%. Vancomycin-Resistant Enterococci, that's a bacteria that can cause urinary tract infections, resistant to most oral antibiotics. FQRP is fluoroquinolone-resistant Pseudomonas. That's a bacteria we see a lot of in the hospital. So you can see these are these strains of bacteria are spreading rapidly.

This is a map that shows that nasty Klebsiella, the one the LA Times article was referencing. And this is in November of 2006. First reported cases were in New York. As I mentioned, a lot of these were imported. And then the states with yellow had some. This is where we are now. Okay, so just five years. Look how it spread across the whole country. Why isn't it here? Simply, probably because there aren't that many people living there and there's not as much healthcare contact.

The scariest one of all is something we call NDM-1 E. coli. In 2010, we had reports of a new resistant mechanism spreading from India. This is a strain of E. coli that's resistant to all antibiotics except that same one, colistin, that old one, or another one called tigecycline. But 10% of the strains were resistant to both of those drugs also. So truly pan-resistant, meaning literally we have no antibiotics to treat them. And this is our worst nightmare because E. coli is a common bacteria. In fact, E. coli is the bacteria that causes bladder infections. So a picture, a scenario where a healthy 22-year-old goes to her OB-GYN with a bladder infection, and we have no antibiotics to treat it. It's very scary.

Last year, I took care of a very prominent businessman, as vice president of a company. He went to New Delhi, India, for a business trip. He stayed in a very nice five-star hotel. He didn't do anything exotic. He ate his meals in the hotel restaurant. He was there for four days and flew home. Developed prostate infection with this particular strain of E. coli, and we had nothing to treat him with except an intravenous antibiotic. So he basically ends up on six weeks of an intravenous antibiotic at home, completely sidelined him and changed his life for, for six months dealing with this infection. Pan-resistant superbugs is what we're thinking about now.

Brad Spellberg, who does similar research to myself down at Harbor, had this great quote in the New York Times. There was a nice article a year ago on antibiotic-resistant infections, and he said, "For these infections, we're back to dancing around a bubbling cauldron while rubbing two chicken bones together." I always wanted to go into medicine, but I was never much of a dancer.

Antibiotic resistance is not only a problem to patients, it's a problem to healthcare systems in general. This slide shows you some very common infections that we're seeing nowadays and the increased risk of death. This is measured as odds ratios. So if you have, for example, a VRE infection, you have 2.1 times the odds of the risk of dying compared to if you didn't have a resistant VRE infection. Adds length of stay to your hospital stay and adds huge amounts to your healthcare costs. If you have, for example, a resistant Enterobacter infection, that's something like one of those nasty E. coli, five times the risk of death, an extra nine days in the hospital, and $30,000 in costs. All of this adds up to around $30 billion annually. Overall, there's 2 million people in the United States that get healthcare-associated infections. Those are infections acquired in the hospital, and 100,000 of those people die as a result, which is more than AIDS, breast cancer, and traffic accidents combined. And I don't single those out to belittle their causes by any means, only to show that the burden of this is so huge, and yet awareness, advocacy, fundraising, etc., is minimal.

This is not a battle that we can win. And the reason for that is simple. This slide shows microbes versus humans. If we look simply at the number on Earth, microbes outnumber us by a factor of 10 to 22. In fact, not just number, but their mass. 10 to the eighth actual metric tons of mass is bacteria compared to humans. Bacteria can divide in 30 minutes, where for us it's around 30 years on average. And the time that they've been on Earth, 3.5 times 10 to the nine, a factor of a thousand more simply than we've even been around.

The next thing is that bacteria can exchange their genes with each other. So if you have resistance in one strain of bacteria, it can spread to another. And this can happen on what we call the, the phylum level. Now, those of you who took biology in, in high school, you remember Linnaean taxonomy: kingdom, phylum, class, order, family, genus, species. Humans can only exchange genetic material between species. Okay, that makes sense, Homo sapiens. Okay. Microbes can exchange genetic material between phylum. As an example, the equivalent promiscuity that would require capability to exchange DNA for humans: family Hominidae is chimpanzees. So for us to be able to exchange DNA with chimpanzees, order Primates would be orangutans, class Mammalia would be grizzly bears, tiger, walrus, killer whale, which would actually be pretty cool. And then phylum Chordata would be falcon, great white shark, frogs, or crocodiles. So bacteria are able to exchange genetic material with, with, uh, different phylum. So they're completely genetically dissimilar, yet they're able to exchange genetic material. Microbes have been creating and defeating antibiotics for 20 million times longer than we've even known antibiotics have existed. So Joshua Lederberg, who's a Nobel laureate in science, 2000, said, "The future of humanity and microbes will likely evolve as episodes of our wits versus their genes."

So what contributes to resistance among bacteria? Because if we understand that, then we know how we can solve the problem. Well, obviously, a big part of this is evolution and selective pressure. You take an antibiotic, the bacteria that are there mutate, they learn how to become resistant. A lot of this happens naturally without humans even being involved. In fact, antibiotics evolved initially as a way for bacteria to kill each other. Misuse of antibiotics, that's a big part of resistance these days, and that's what we're going to spend most of the rest of the time talking about. Patient expectations, certainly is part of it. Every time you get a runny nose or a little cough, you run to the doctor and get put on antibiotics. Self-medication or poor compliance with therapy. "I got a little bit of a runny nose. I've got some antibiotics laying around from the last time when I didn't finish the full prescription. I'm going to start taking it again." And then inappropriate prescriptions by doctors, both on the inpatient and outpatient side.

The hospital environment plays a big role. We have highly susceptible patients, in particular at a place like UCLA, but even everywhere now. Even if you go to Providence St. Joe's or any other community hospital, the patients are sick nowadays. To get into a hospital, you've got to be pretty sick. We're not talking about run-of-the-mill general, you know, pneumonia and kidney infections now. Everybody's got complicated problems. We have intensive and prolonged antibiotic use in the hospital environment. And then we have cross-infection. Well, infection control. So patient in bed one has a resistant bacteria. Doctors, nurses don't do a good job washing their hands, or maybe someone's coughing or whatever, and it spreads. Spreads to other patients. And then, lastly, and something I think that's very underappreciated, is the agriculture and veterinary use of antibiotics. Which in the United States, 85% of antibiotics are actually used in agriculture, and most of those are the same ones that we use in humans, Cipro, things like that. Not going to talk about that because that's a whole other lecture, but that's something to think about.

Antibiotics are widely abused. Studies have consistently shown us that 30% of hospitalized patients at any given time receive antibiotics. That number is more than 60% at UCLA. Why? Because we have so many transplant patients and other complicated medical patients. But just think about that, six out of 10 patients at UCLA are getting antibiotics. Okay, we have about 520 beds, so you can do the math and think how many people in the hospital are on antibiotics at any given time. Studies have shown that around a third to a half of all antibiotics are either inappropriate, meaning the wrong antibiotic, or unnecessary, meaning not even needed at all. The patient doesn't even have an infection. Antimicrobials account for upwards of 30% of hospital pharmacy budgets. We spend $8 million here at UCLA on antibiotics every year. And inappropriate and excessive use leads directly to bacterial resistance. We talked about that. And then things like C. difficile. That's a bowel infection that you get as a direct result of abuse of antibiotics. And even to morbidity and mortality. Antibiotics are not benign medications. They have side effects. Some of them cause kidney damage, they cause allergic reactions, they have interactions with other drugs and can cause cardiac arrhythmias, for example. Increased costs. Some of these antibiotics ain't cheap. $200, $250 a day. You put a patient on that for 10 days, that's $2 grand right there. So all of this drives up the cost.

Then there's also ecologic consequences. Vancomycin is an antibiotic we use to treat gram-positive infections like Staph, like MRSA. UCLA, this is our utilization of vancomycin over the last decade. And you can see we basically have doubled our use over the last 10 years. Okay. Now, some of that's appropriate. We've had more MRSA in the community, so some of that is okay. But a lot of it's not okay. So abuse of vancomycin leads directly to vancomycin resistance. And in particular, a particular strain of bacteria called Vancomycin-Resistant Enterococci, or VRE. So we used too much or unnecessary vancomycin, we get more VRE. And in fact, when I put VRE on the same graph in red, you can see that they're parallel lines. Okay. One of the antibiotics we use to treat VRE is something called daptomycin. And that's that antibiotic that costs $200 a day. We put daptomycin on that same graph, it's also a parallel line. So if we want to stop using the expensive antibiotic, we got to fix the VRE problem. And the only way we're going to do that is to use less vancomycin.

This is not a new problem. It's a problem now because it's a crisis because we're running out of antibiotics. But this is not a new problem. This is a quote: "The prescriber is under great pressure to prescribe the newest, best, broadest antibiotic preparation, prescribe it for any complaint whatever, quickly, and preferably without worrying too much about specific etiologic diagnosis or proper indication of the drug." This is a famous microbiologist named Ernie Jawetz. And he said this in 1956. Okay, it's been 50 years. We can go back even further. "Microbes are educated to resist penicillin, and a host of penicillin-fast organisms is bred out. In such cases, the thoughtless person playing with penicillin is morally responsible, morally responsible for the death of the man who finally succumbs to infection with a penicillin-resistant organism. I hope this evil can be averted." Who said this and when? Any guesses? Nobody? Does a picture help? That's Alexander Fleming. What did Fleming do? He discovered penicillin. He said this in a New York Times editorial in 1945. Okay, so this is just a few years after penicillin was starting to be used. He already was recognizing the problem. And then look, I think this is fascinating. "The thoughtless person playing with penicillin is morally responsible." Do we think about antibiotic use in those terms nowadays? We sure don't.

It's fascinating, though. The problem that we have is the dual battle between the needs of society and the needs of my patient. And what I mean by my patient is, I'm in the room with a patient in front of me. From a societal level, we can all agree that antibiotics are widely overused and abused. We can talk about drug resistance, we talk about the huge cost to the healthcare system of resistant bacteria and of antibiotics. And we can say, "Of course, 100% of patients with bronchitis have viral infections, they don't need antibiotics at all. 80% of patients with ear infections don't need antibiotics." On a societal level, we make those statements and we all agree with them. But then there's my patient in, in the office in front of me. And yeah, you've been coughing for two weeks. Yeah, your chest X-ray is totally normal. But I, yeah, here you go, here's a prescription for antibiotics. I'm just, I'm not sure what it is, but maybe, maybe it's an infection, it'll make you feel better. So we have diagnostic uncertainty at the level of a patient. Pressure to prescribe. The patients will come to see us and they say, "You know, I really want an antibiotic." That's especially true in pediatrics. There's a very common misconception that if it's green, it must be bacterial. The mucus is green, the cough is green, it must be bacterial. It's not true. But parents, patients, they, they see that and they have pressure. And the doctors feel it's easier to write a prescription than it is to explain to them. Doctors would rather make an error of commission than an error of omission. What does that mean? They would much rather do something to a patient and in doing it be wrong, than to leave something out and make a mistake. And by, by omitting something, for example, if I gave a doctor a hypothetical that you have a patient who might have a life-threatening infection, would you like to withhold antibiotics and do nothing and watch and see how they do? The doctor is going to say, "Of course not, that's silly. I'm going to give the, throw the book at them and make sure that I'm giving them antibiotics." I said, "What if giving that patient the antibiotics resulted in Clostridium difficile, a life-threatening infection of the gut, leading to that patient needing to have emergency surgery for a colectomy and having their bowel removed?" The doctor's still going to say, "I'd rather be on the side of giving them antibiotics because I don't want to miss a life-threatening infection." It's an error of omission versus commission. And then, lastly, and this is especially true at UCLA, "My patients are different." We hear that all the time. "I hear everything you're saying, Dr. Yuslin, this is so true, it's so important, now you're doing really great stuff, but my patients are different, so this doesn't apply to them." So we have this battle between societal needs and patient needs.

Why do doctors have such a hard time using antibiotics correctly? Well, there are a lot of reasons. Simply, there's a high number and complexity of the drugs. There's dozens of antibiotics, and we dose them differently, and they get to different parts of the body differently. Some are better for urine, some are better for brains, some are better for lungs. High number and complexity of infectious syndromes and the pathogens. And then, just to keep us on our toes, the microbiologists like to change the names of the bacteria every 10 or 20 years, just to keep us guessing. Poor training in antibiotic use. Okay, we get a couple lectures in our medical school, and really, that's about it. The rest is kind of learn as you go. Now, compare it to, for example, chemotherapy. Now, I would never say that antibiotics are as toxic as chemotherapy, but you would never, ever find a first-year orthopedic surgery resident saying, "Well, you've got breast cancer, let me write some chemotherapy for you and see what happens." But that's the attitude we all take about antibiotics, especially in the hospital. You've got a skin infection here, let's try something and see what happens. Again, antibiotics are not chemotherapy, but anybody can prescribe them, and we have poor training in how to use them. Empiricism for ill patients is a big driver in the hospital. What I mean by that is, throw in the book at patients because you don't know what else they have. Somebody comes into the intensive care unit with a fever in the middle of the night, you don't know what's going on, you're going to knee-jerk and throw antibiotics at them. And some of that's okay to do that if you're an intern. One of the scariest things is fever in the middle of the night. So all of this leads to a vicious spiral. The doctors feel like they have to get it right at all costs. They don't want to get sued. They're afraid that they're going to miss an infection. We have inadequate rapid tests. It takes us three to five days to get some of our results back, our culture results back. And even when we get those tests back, we don't really believe the results sometimes. Defense of medicine and patient expectations. All of this drives up cost, drives up bacteria resistance, makes us want to use newer, newer drugs and more broader drugs, and all of this is a vicious spiral.

This is a study I want to briefly mention looking at unnecessary use of antibiotics in hospitalized patients. And they did this study prospectively in an ICU. And a full 30% of the antibiotic days of therapy were deemed unnecessary. And the reasons were: firstly, that the duration was longer than necessary. So typically, for example, somebody who's got pneumonia in the ICU, we treat for seven days. So if you get 10 days or 14 days or something like that, that's longer duration than necessary. Secondly, was the patients had a non-infectious or non-bacterial syndrome. So they had congestive heart failure, or they had asthma, or something where they truly didn't even need antibiotics. And then, lastly, was treatment of what we call colonization or contamination, meaning the bacteria is sitting there but it's not actually causing an infection. But even though I spent all my time worrying about using antibiotics in the hospital, it's really the outpatient setting where the biggest abuse is.

These are data from the CDC. And the total width of the bar is the number of prescriptions in millions for various common infections. And then the proportion of those that's green is the proportion that's unnecessary. So for the common cold, 18 million antibiotic prescriptions in this country each year, 100% of those unnecessary. Okay. So again, you see, I'm worried about Mr. Jones in bed two and why we're throwing six antibiotics at him, but this is really the bulk of the problem.

So let's talk briefly about new drug research and development. We are in an absolute crisis with our new drug R&D. And the simple matter is that we aren't developing new antibiotics. This slide shows new antibacterials developed over the last 30 years. Back in the '80s, there was new things coming out every, every other year. It was a very exciting time to be an infectious disease specialist. The last few years, we've basically had, have had four antibiotics. We've had telavancin, ceftaroline, tigecycline, daptomycin, and that's basically it. And none of those have been antibiotics that treat the resistant gram-negative infections that we're really worried about. In fact, if we add all anti-infectives, that means anti-fungus medicines, HIV medications, virus medicines, all of that together. Back in the '90s, there was new HIV medicines coming out every few years. It was very exciting. But even then, look where we are now. And the overall trend going back to 1980 has been decreased.

This is the current pipeline for gram-negative agents. Again, that's back to those are to treat those resistant E. coli and other bad, nasty bacteria. There are a bunch of drugs in pre-clinical testing, and there are none in phase one, two, or three clinical trials. What does this mean? Well, this is the timeline for development of a new antibiotic. You have your pre-clinical testing, and then you have your IND filing, investigational new drug with the FDA, and then a phase one, phase two, and phase three clinical testing, FDA review, and a product launch. That all in all takes about 10 years. Okay. Remember, a bunch of drugs pre-clinical, none in phase one, two, or three, which means even if today we had an IND filing, it would still be 8 to 10 years before we had a new antibiotic. In contrast, at the same time, 67 new drugs for cancer, 33 for inflammation and pain, 34 for metabolic, etc., etc. Why? Look, anti-neoplastic and immunomodulating agents. If you're an oncologist right now or a rheumatologist, boy, it's like being a kid in a candy store. Look at all these new drugs that are coming out. And, and contrast that to the graph of the anti-infectives. They're basically mirror images of each other.

Why is antibiotic development decreasing? There are a lot of reasons. First is that it's a small market. Antibiotics work well and fast. I give you a prescription, you take it for a week or 10 days, or maybe at the most six weeks, and then you're done. Hopefully, you never take it again. Then compare the number of patients with a drug-resistant E. coli compared to the number of patients with diabetes, or emphysema, or osteoporosis, or depression. Those are chronic, long-term conditions, lifestyle issues. If you have a, if you have a cholesterol problem, you're probably going to be taking that medication every day for the rest of your life, certainly not for 10 to 14 days. Second is the long-term potential is limited because the bacteria become resistant. Okay, the, the drug works for maybe 10-15 years, and then it's not working anymore. Whereas the millionth dose of Lipitor for cholesterol works exactly the same as the very first dose. So if I'm Pfizer, or I'm Merck, or I'm Johnson & Johnson, why am I going to spend my billion dollars, which is how much it costs to make a, to bring a drug to market, on developing an antibiotic? Where's my return on investment for that, that investment? And the simple answer is that it's not there. Second is the way that doctors use antibiotics. If there's a new cardiac drug, it'll be studied in, for example, the New England Journal with a 4,000, 5,000 patient study. It'll have a very catchy name, and it'll be a big news, and it'll come out, and the cardiologist will say, "Here's a new drug, everyone use it." Whereas if we in infectious disease get a brand new antibiotic, we say, "Here's a new drug, now nobody use it." So again, if I'm Pfizer, why am I going to spend money on this?

How are we going to stimulate antibiotic research and development? Well, we have to improve return on investment for the drug companies. So one way is to simply decrease the cost of development. And that could be things like tax credits, or grants, or contracts, or liability protection. Secondly, is to increase the income linked to antibiotics. For example, novel market exclusivity or patent extensions. Antibiotics are still relatively inexpensive. Even that $200 a day antibiotic, if you compare that to some of the costs of cancer drugs, for example, it's not that expensive in the greater scheme of how much some drugs cost. The problem is, is that there's no one limiting step. There's a whole bunch of them. And so there's going to be a variety of incentives that need to be undertaken. And a lot of this is going on at the federal level.

The bottom line, however, is we can't make companies develop new antibiotics. We have to make them want to develop new antibiotics. So the premise really needs to be to think about antibiotics as a resource, in fact, a pressure-limited resource, just like fisheries, forestry, and energy, which is that they change depending on how they're used. So that means, just like fisheries or forestry or energy, we can't just conserve, we also have to restore.

So going back to some history. This is Walsh McDermott, who was the first president of the Medical Board of the National Academy of Sciences. And this is 1960. "With today's antibiotics, it is possible to place in the hands of a barefoot, non-literate villager more power to affect the outcome of a critically ill patient than could have been exerted by the most highly trained urban physician 25 years ago." So how do we fix the problem? Well, there's only two options. Just new drugs, and we just talked about why that's going to be a problem. And then there's using the drugs we have better. Dennis Maki is an ID doctor, and he says, "Developing new antibiotics without mechanisms to ensure their appropriate use is much like supplying your alcoholic patients a finer brandy." Okay? In other words, simply creating new antibiotics unless we're teaching people how to use them better is just like giving new brandy to an alcoholic patient. As I said, around half of antibiotic use is either unnecessary or inappropriate. And that is true no matter where you look. If you look at places like UCLA, community hospitals, VA, inpatient, outpatient, and at UCLA, at least 60% of our patients get at least a day of antibiotics. So resistance is a complex problem, which means that the solutions to resistance have to be complicated too.

So what I do is called antibiotic stewardship. And of course, a steward is a caretaker of a resource. Okay? It could be stewardship in the religious sense, it could be a wine steward. This is antibiotic stewardship. And the goal really is to optimize antibiotic use through appropriate selection, picking the right antibiotic, giving it at the right dose, and giving it at the right length of time. And our goal is really to improve clinical outcomes. Yes, we save money when we save antibiotics, but the goal really is to reduce emergence of resistance, limit adverse events related to antibiotics, like kidney failure, and minimize the risk of some of these other consequences, such as the C. diff, this bad gut infection. And a stewardship program is really complementary to an infection control program. And the way I think about it is that if the patient in bed one has a nasty infection, infection control says, "Well, we want to make sure it doesn't spread to the patient in bed two." But the stewardship program says, "Well, why did that patient in bed one get that resistant bacteria to begin with? And perhaps it was all those antibiotics that maybe that patient didn't even need."

This is what the CDC has come out and said as their 12-step program to prevent resistance in hospitalized adults. So this is the CDC's approach, and I think it's a very good one. Now, I think the first step of any 12-step program has to be to stand up in public and say, "Hi, I'm UCLA, and I have a problem." CDC doesn't have that at their first step. Their first step is prevention, which means vaccination. We don't do a very good job, especially in our elderly patients. We do a lousy job of giving them pneumonia and influenza vaccination. But we know those are the most common infections, and we know that once you get into the hospital, you're very likely to pick up something else in there. So vaccination is step one. Two is getting those catheters out. Both the kinds of catheters we put in bladders, Foley catheters, but also venous catheters in our ICUs. It's not uncommon for patients to have three, four indwelling catheters in, and they're a risk for getting bacteria in the blood. Urine infections, a lot of those are unnecessary. There was a very famous study a few years ago where they looked at which healthcare workers knew if their patient had a bladder catheter. And nurses, it was like 88% knew that their patient had a bladder catheter. And then medical students, it was like 70%. Residents, it was about 50%. And they got all the way down to the attending physician, who's the one in charge of that patient's case, 26% knew that their patient had a bladder catheter. Appalling. Okay. So we need to do a better job of getting these catheters out.

The next steps are to diagnose and treat infections effectively, which means to target the right bacteria. It's a very difficult thing to do, but often in the hospital, we take a shotgun approach to treatment of infection. Mr. Jones has a fever, shotgun, we throw the book at them. So we need to do a better job of educating our doctors and helping them have the resources to know what antibiotics to use, which means accessing the experts. That means infectious disease consultation in the hospital. Using antibiotics wisely, which means practice antibiotic control, and we'll talk about that briefly. Being aware of local data. Every institution is different. If you go to Cedars-Sinai, the types of bacteria they have are very different than here, and very different from the VA. Problem becomes, if you're a resident and you're rotating at different hospitals, or your patient is transferred from one hospital to another, it's difficult to be aware of what's going on locally. Treating infection, true infection, not just a contaminated culture. And treating infection, not colonization, that's when the bacteria is sitting there but not actually causing an infection. Know when to say no to vancomycin. That's our number one used antibiotic at UCLA. And then, lastly, is to stop the treatment when the infection has been cured or is unlikely. So if I find out Mr. Jones came in and their blood pressure was really low and they had a fever, you know what, it was great that you put Mr. Jones on some antibiotics, but it turns out he had a massive heart attack, and that's why his blood pressure is low and he had a low-grade fever. So you can stop those antibiotics now.

And then the last two steps are to prevent transmission, which means isolating the pathogen, that means putting patients in isolation, and breaking the chain, which is our hands in healthcare workers. So hand washing. So steps five through ten are all what I would consider antibiotic stewardship. Okay. Now, I don't want to spend a lot of detail talking about how one does it, only just to show you conceptually. There are a lot of ways you can intervene to improve antibiotic use. So this is a model, basically showing the patient coming into the hospital on day one. And let's just say that that patient has sepsis. That's a pretty common infection in the hospital. And they get put on these three lines here, three different antibiotics, all the way to day three, when now hopefully we've got the results of some of our microbiology lab testing, and we can figure out exactly what the patient has. So you can intervene on the front end here, on when that patient comes in. You can help out with choosing the right antibiotics for that patient. And that could either be human decision support. And some places actually have that. When I was at the Mayo Clinic, they actually had an antibiotic hotline. And if I'm that first-year orthopedic intern, I'm great, I know all about broken bones, I may not know how to treat sepsis. I can pick up the phone and reach somebody on the phone and say, "Hey, I've got this patient, what do you think?" So that's human decision support. Other places have computerized decision support, where the computer actually helps to guide you. You say, "This patient has sepsis, and they're coming from a nursing home, and they're allergic to this," and the computer helps tell you what to do. You can have a restricted antibiotic formulary. And that's what a lot of programs back East do. That's what they do at Johns Hopkins and University of Pennsylvania and Tufts and places like that, where if you want to prescribe some of these widely abused antibiotics, you have to pick up the phone and get permission from somebody, or you have to fill out a form and it has to go to a pharmacy and get stamped to be approved. Or you have guidelines and protocols. So you say, "This is how we treat pneumonia at UCLA, and this is our order set, and this is how we follow it." So there's a lot of things you can do on the front end. You can also intervene on the back end. So people could start whatever they want, but now on day three, you can say, "You know what, it's great that you started those three antibiotics, but your patient's doing better, and now we know that he has a Staph infection, so we can stop those other antibiotics, we can switch him to this antibiotic, and the patient can go home." So you can help in to interpret the data and help decide if there's infection or no infection, interpret the laboratory data. You have opportunities for what we call de-escalation, meaning that that patient was on broad coverage, and now you can switch to narrow coverage, or you can switch from intravenous to pills.

Can a stewardship program improve outcomes? Well, the answer is, it depends on what kind of outcome you're looking at. The idea is, is that we do some sort of intervention, that that intervention leads to either a decrease or improvement in antibiotic use, and then that leads to a decrease in antibiotic resistance. So there are really good evidence that this, this thing happens. Not as good evidence as that happens. Now, I don't want to spend a lot of time talking about it, but I want to show you briefly that measuring and studying resistance is extremely complicated. Here we are at UCLA, our tertiary hospital, and we have patients transferred constantly from community hospitals, nursing homes, VA, community. Some of these patients are getting home care, maybe they're getting dialysis, or chemotherapy, or wound care at home. They've got children who are going to day care. Maybe they're traveling to foreign countries where they can get antibiotics for 10 cents a day, or they're getting exposed to infections like in India. The patient I talked about, they're eating food from animals where their feedlots are using antibiotics. So if we just look here and measure resistance here and say, "Hey, we fixed the problem here at UCLA," we're missing the 30,000-foot view of the problem of resistance. So there are some data that that antibiotic stewardship programs can decrease C. diff, can decrease resistant gram-negatives and VRE. So, uh, just to show you one example, because I really like the graphically way, the graphical way that they did this. This was a hospital that had a huge problem with C. diff, again, that's that nasty bowel infection that you get as a complication of overuse of antibiotics. And what happens is that the antibiotics kill the normal bacteria that are in your intestine, and as a result, this bacteria, which is a spore, can come in, set up shop, and cause severe, horrendous diarrhea. It's not an uncommon problem in hospitalized patients who've been getting lots and lots of antibiotics. So in this particular hospital, they had a huge problem with C. diff. And the blue bars here represent the number of cases that they had. In fact, over about a year period, they had a tripling in their C. diff rate. Okay. So they implemented very, very strict infection control measures. That's that red arrow right here, in September of '03. And that was the very first time a patient had diarrhea in the hospital, they went into isolation. That's the yellow gowns, gloves, the whole thing. Very first loose bowel movement, they were in isolation. That's draconian. That's that's difficult. You can imagine the nursing burden to have to deal with all that. But you can see that despite doing that, their C. diff rate didn't go down. Okay. Infection control didn't solve the problem. So then they got creative. And then in April of '04, they implemented a very strict antibiotic optimization intervention. Now, the gold bar here is the total amount of antibiotics that they were using. And you can see that they had basically a 50% drop in their antibiotic utilization. And lo and behold, C. diff, which I told you is directly caused by overuse of antibiotics, immediately fell. And then, interestingly, around, this is around, I don't know, January of '05, they actually stopped their antibiotic optimization, but yet their antibiotic use and their C. diff rate remained low.

So what we've done at UCLA is a back-end approach, a prospective audit, meaning we see the patients, follow them prospectively, and then we provide feedback to the prescriber. So we say, "Hey, orthopedic surgeon, great, I'm glad you started those three antibiotics, but we can switch it to this one, it'll work just as well, in fact, it's available as a pill, so your patient doesn't need intravenous and they can go home." So we do a lot of things that are simple, like simple switching from intravenous to oral. We've done a lot of education and marketing. I've given lectures like this one to numerous groups. In fact, tomorrow I'm giving this lecture to the neurology residents. We're working on improving our availability of expertise at the point of care. We've developed an antibiotic handbook and a web app, and I'll show you that. And the idea here is again, what works for treatment of pneumonia at Johns Hopkins or Tufts or Cedars-Sinai, it may not work here at UCLA because we have different bacteria. So we're developing local guidelines. So someone who's at two o'clock in the morning and they've got a septic patient, they have a resource that they can go to to figure out what to do. And then, just like at the Mayo Clinic, we're working on an antibiotic hotline. So someone can pick up the phone and reach us. And then, lastly, is data monitoring and transparency. Because I think, in general, most doctors are very supportive of our efforts. They simply don't know that they're overusing antibiotics. Our stewardship program is at the heart of many different areas in the hospital. We have to work closely with our infection control colleagues, with pharmacy, micro, our ID clinicians, etc. The way our program works, briefly, is we get a daily antibiotic report. We identify patients who maybe have to have a potential intervention. And then we supplement that with practice guidelines and look for opportunities to do things like streamlining and education. Then we do a focused patient record review. And then we either do no intervention, do something routinely, or occasionally we have to seek additional clinical input. And we pick up the phone and we call the team and ask them why their patient is on antibiotics. And then we leave a recommendation, which is always billed as an educational recommendation in the patient's medical record. And the idea here is not to be punitive. These are non-binding recommendations. Their idea is to be educational. So we say to the orthopedic surgeon, "Perhaps you weren't aware that those two antibiotics are overlapping in what they do, and it's not necessary to use both of them at the same time."

We've developed a mobile web app. And I want to show you this. Those of you who are interested, if you go to uclamobile.org, you can make a button on your iPhone, uclamobile.org, right there. And then that will take you here. And the nice thing about antibiotics, that they start with the letter A, so we're at the top of the list. So you can click on "Antibiotics Guide." And then that's a web app. It's going to have information about how to treat pneumonia, how to treat C. diff, how to treat all of these other things. An idea again is to be, if that's that orthopedic surgery intern at two o'clock in the morning, they've now got a resource of something they can use. And I don't mean to pick on orthopedic surgeons, by the way. I have a lot of respect for them. That just, they're a good example, simply because they're so different from infectious disease in their specialty. The second thing is, we have now have a website. And if you go to the MenNet home page, we're right now at the very bottom of Clinical Systems, Antimicrobial Stewardship Program. And you can go here and find some up-to-date information and some news. But there's a link right here called Guidebook. And it's essentially the same content, but it's got information about how to treat various common infections. So our program's working.

This is our antibiotic utilization at UCLA over the last two years. Now, I told you vancomycin was our most commonly used antibiotic. And we measure antibiotics in days of therapy per patient day per thousand patient days. Okay? What that means is that if you get a dose of vancomycin, that's one day of therapy. And then we normalize it by thousand patient days, because of course, each year we may have a different number of admissions to UCLA. So you'll see back in 2009, we were around 200 days of therapy of vancomycin per thousand patient days, or crossing off a couple zeros, around 20% of UCLA patients got vancomycin. Unbelievable. So now we're down to around 15. So we've had a substantial decrease, which is great. And our overall total antibiotic utilization is down by about 15%. So we're making great strides.

To close, I'd like to include this comment from Dr. Paul B. Batalden, who's a very famous researcher on basically change processes and innovation at Dartmouth. He says, "Every system is perfectly designed to produce the results it gets." That's very true, and that's a very profound statement if you think about it. So if we're fine with skyrocketing resistance and plummeting new antibiotic R&D, and with patients dying of untreatable infections, let's keep doing what we're doing, because our current processes are perfectly designed to cause this. But if not, the time has come to admit that the ways we have developed, used, and protected antibiotics for 70 years have failed. Our antibiotic resource is dwindling, and we need new, innovative solutions, because simply retreading the same tired half-measures is no longer enough.

It's a closing graphic. I want to show you this slide that shows the mortality rates from staphylococcal bacteremia over time. Staph is one of our nasty bacteria. If you get Staph in your blood, it's very serious. Back in 1937, in the pre-antibiotic era, 80% of patients died. Within a decade, look at this, penicillin, down to 30%. Amazing how that worked. Within 10 years, we saw penicillin-resistant Staph aureus, and we were back to 50% mortality. Then methicillin came along, semi-synthetic, theirs, back down to 30%. Then in the last few decades, we've had Methicillin-Resistant MRSA, and now Vancomycin-Intermediate Staph Aureus. And look, we're basically almost exactly back to where we were 70 years ago. So we've come a long way, and yet we've lost a lot of ground.

So I'll stop there and tell you not to forget to take a handful of complimentary antibiotics. You.