- 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)