Resistance Movement: Drugs, bugs and the fight against über-germs – Longwood Seminar

If everyone could take
their seats, please. If you don’t have a
seat, please find one. We’re about to begin. Good evening, everyone. How are you? Good! All right, how are you? Good. Yes. Welcome to the 17th
annual, I guess you can say, Longwood Seminars. Today we are going to be talking
about the resistance movement– drugs, bugs, and the
fight against uber germs. Audience members, as well as
the social media community, actually had a hand in
choosing tonight’s topic, and it was one of
the most popular. So thank you for doing that. [APPLAUSE] How many of you have
attended this seminar before? Oh, wow, quite a few of you. How many is this
your first time? Nice. Welcome, so glad you came out. So we’ve also expanded not
just beyond these walls here at the News Research
Building, but we also have a very thriving
social media community who watched this
event through Livestream. So say hello to the people
globally– if you want to wave, they can see you. We might not be able to see
them, but they can see us. So welcome to all the global
community that is tuning in for this presentation. Before we begin, I just
want to make a couple of housekeeping announcements. I know, boring, right? So one, I know a
good many of people here are interested in a
certificate of completion, which if you attend three
of the four seminars, you will receive. PDPs for teachers are available
for those that attend all four of the seminars. And when you entered
in today, you received a question and
answer postcard for you to write your questions on. Please feel free, we have staff
that will be collecting cards throughout the presentation to
answer any questions that you may have. We will be giving
them to the panel, and they will address those
towards the end of the talk. Videos and reading materials– I know there are a
lot of people that were wondering about the
supplemental materials that will go to this seminar– they will be available
online beginning tomorrow at the website
that you see here above. And then also if you
have Twitter fingers, that’s a good thing,
because we are actually having a conversation
on Twitter about this. Please visit
hashtag #HMSMiniMed. And then one last thing is if
you could put your cell phones on silent, that would be great. It’s OK if they vibrate, we
just don’t want them to ring. Thank you so much. And without further ado,
I want to introduce to you our main topic, which is
the resistance movement– drugs, bugs, and the
fight against uber germs. With many bacteria becoming
impervious to drugs, new approaches are
needed to combat the rise of antibiotic resistance. This evening I’m thrilled to
welcome four of Harvard Medical School’s leading
scientists and clinicians to discuss the history of
drug resistance, how bacteria becomes able to shrug
off the medications we use to treat disease, and
ways to address the crisis. I would like to welcome
our first speaker and moderator for this
evening to the podium, and it is Mr. Bill Hanage. He is associate
professor of epidemiology at Harvard University and T.H.
Chan School of Public Health, and is also a
faculty member here in the Center for
Communicable Disease Dynamics. Bill? Thank you. Thank you. [APPLAUSE] Thank you so much, [INAUDIBLE]. Thank you. And also thank you all
because you selected this. This is a very important and
very, very, very important topic, because I think
we’re going to cover over the next hour or so. Could I just get started by
asking you to reach over, I know this is
going to be a little like a revivalist
meeting, but if you could reach over and shake hands
with the person next to you. This is not an attempt to
get you to transmit disease. And then it’ll all
become clear later. And then on the
other side as well, yeah, like that, that’s
it, you guys as well. Thank you. Great. This is all going to
become clear later. This is not– and if you’re
watching on the internet, shake hands with
whoever’s nearby. So I want to start
by asking what would a world without
antibiotics look like? What are antibiotics? Well, they are the
drugs that we use to treat bacterial infections. Bluntly, they kill
bacteria, or at least stop them growing long enough
so that the immune system can kill the bacteria. They were first
discovered in the 1930s. Famously, penicillin
was found by Fleming– we’ll come back to him later. It was only actually developed
as a sort of useful therapeutic during the Second World
War by Florey and Chain. But since then, people
have estimated– and I don’t like coming up
with big numbers off the top of my head because there’s a
lot of uncertainty in them– but people have
estimated that penicillin has saved 200 million lives. Regardless of whether
that’s exactly correct, it’s a big number. So a lot of people think
that using antibiotics would take us back to
something like this. This is a Bruegel painting
called The Triumph of Death, and it’s based upon the
catastrophic epidemics of Yersinia pestis– plague– which bedeviled
Europe in the pre-modern era– they could take away a
third of the population. And a lot of people think
that– and it’s readily treatable with antibiotics. A lot of people
think that that’s what losing antibiotics
would be like. But actually, I think it’s
worth thinking a little bit more carefully about what
the value of antibiotics is to modern medicine. And it’s not so much that
it’s fighting the Black Death, it’s that it makes so many
things in modern medicine possible. For instance– whoa, that was– I was the first person to
make a mistake with this. There we go. Transplant surgery
or cancer therapy frequently require that we
suppress the immune system. And if we suppress
the immune system, that leaves the body prey
to bacterial infections. If we cannot treat those
bacterial infections, people run the risk of
very serious consequences– death, bluntly. Basic procedures or basic
things that we might not have thought about. I mean, a burst appendix–
to be sure– is not something that you want to happen, even
now, because it will let loose a deluge of bacteria
into your body that you don’t really
want to be in your body– you want them in your appendix. If they are resistant
to antibiotics, then we’re going to be
unable to treat that, and that could become deadly. And then there are the things
that we find in the community– the pneumonias, the gonorrheas,
and the tuberculosis. Tuberculosis is something
that one of our later speakers is going to cover in depth. As these become
untreatable, then we run the risk of being
able to pick up diseases within the community that could
kill us or leave us infertile or many other
negative consequences. Just to put some numbers
on it, a few years ago, I was asked with others to– I went to a meeting of the
World Health Organization, and they said, what’s the
burden of antibiotic resistance? And, as I said
earlier, it’s very hard to come up with
accurate numbers, but the numbers are large. We estimate that worldwide–
this is from the Wellcome Trust– around 700,000 deaths
occur every year from antibiotic resistance–
around now, this is. In the United States
there are about 2 million serious antibiotic-resistant
infections every year, and about 23,000 deaths. To put that into
context, somebody will die while I am talking
to you now, probably from an antibiotic-resistant
infection. But that’s now. And as we’ve said, this
is a growing problem. Some people have
tried to estimate tried to run the tape forward
to see what the situation could be like in 2050. In 2050, we’re looking at
a world-wide annual death toll of around 10 million. To put it into context,
the 1918, ’19 flu pandemic killed about 40 or 50 million. So it’s not up
there, but this would be an ongoing thing,
not a pandemic which went away and didn’t
come back the next year. The United States–
over 300,000 deaths. And these numbers–
this is a caveat– these numbers were not estimated
by an epidemiologist, which is at least what
I’m a professor of, they were estimated
by an economist. And I don’t want to
be mean to economists, but they’re not have
epidemiologists. Regardless, these
are very big numbers. They’re the things which
sort of [INAUDIBLE]. This is why people like
me are concerned about it. And no matter– I hate to quote
Stalin but he said– a million deaths is a statistic,
a single one is a tragedy. Each one of these
would be a tragedy. And I’m sure many of
you read in January about the lady in Nevada
who came back from overseas with an antibiotic-resistant
blood infection. And it was resistant not just
to the front-line antibiotics, it was resistant
to all 26 that were used to attempt to treat her. And she died. And those are rare, those
infections, and still for now. But just before you
get too comfortable, this is what we
call an antibiogram, or the susceptibility
data, for an isolate that came from a hospital
in the Boston area. And these are the
drugs that we would think about treating
with, and you can see resistant, resistant,
resistant, resistant, resistant– oh, intermediate. [INAUDIBLE] Intermediate
still isn’t good, it still means not
fully susceptible. So this is a problem
which is not remote. It’s coming close
to our door, and we should be thinking about
doing something about it. What makes resistance happen? Why does antibiotic
resistance exist at all? And I’m assuming
that many of you will know the answer to this,
but it’s worth reiterating. Bugs are resistant
to antibiotics because of the same reason
that peacocks have tails– because peacocks with prettier
tails leave more descendants. And in the same
way, cheetahs can run faster are more likely
to catch the gazelle, and they’re going to be able
to feed their little cheetahs. The gazelles that
can run faster are more likely to
outpace the cheetah, and survive to live another
day, and have baby gazelles. Because those properties
are inherited, natural selection means that
these two things are very, very fast, and that this is one of
the great battles of nature. In the same way, bacteria
that are not killed by the antibiotic survive. They live to fight another day. They proliferate
in the population until we have a problem
with antibiotic resistance. It’s evolution. So this was something
that was actually– you would think, since we
have known about evolution for over 150 years, somebody
would have thought about this. And indeed they did– Alexander Fleming,
in 1945, when he was about to be awarded
the Nobel Prize in medicine with Florey and
Chain, who actually did the hard work of making
it into a proper antibiotic you could use in medicine. He gave this interview
to The New York Times, and I will leave you to read it. You can’t quite see it– “the microbes are educated
to resist penicillin.” I think this will get the gist. He makes here that “the
thoughtless person playing with penicillin is morally
responsible for the death of the man who finally
succumbs to infection with the penicillin-resistant
organism.” He predicted it. He knew it would happen. And within years of penicillin
being introduced and used in medicine, it did happen. Fleming discovered penicillin
when a Penicillium notatum– which is a mold– spore of that mold floated
through the window of his lab– which was in the building
opposite where I used to work– and landed on a plate of
Staphylococcus bacteria– like these– and it grew there. And it was able to grow there
because Fleming had gone away on vacation, and he had not
bothered to clear his bench. But when he came back,
he saw that it had grown. And these are actual disks of
paper containing antibiotics, so you can see it. But he found around
it this perfect zone of inhibition, where the
bacteria were unable to grow. And that was how
he first discovered the effect that would lead to
the development of penicillin. I want you to remember
that, because it’s a naturally-occurring molecule. We’ll come back
to that in a bit. The raw material for
evolution by natural selection is mutation. And this illustrates a mutation. DNA double helix– the A’s and
T’s and G’s and C’s, which we all know are nucleotides–
which are shown as colors here– these are identical,
these two DNA strands, apart from
this one, which has generated a single
nucleotide polymorphism– one mutation. Mutations do not happen often. But when it comes
to drug resistance, they happen often enough. There are some classes of
drugs, and some resistances, for which a single
mutation is sufficient. And that might seem unlikely,
but you have to remember that within each of these– these
are several different types of bacteria growing on a plate– within each of these colonies,
there are millions of cells. Now, what you have
to remember there is that even if the mutation
is a one in a million chance, these things are rolling
the dice a million times. So the population
size of these things is such that they have explored
a lot of the evolutionary space already, even
before we get to it. You have around a billion E.
coli in each of your guts– plus a whole bunch
of other things. So you may be wondering,
with some justification, why I’ve put a Sudoku
up in the corner. But one way that
I put this across is that this is a relatively
difficult problem, OK? If I were to give this to
one person in this room, I’m sure– because you’re
all very good at Sudoku– that it would be
solved quite quickly. But if I really wanted
to get it solved quickly, I would take it to Fenway
Park, I would give it to everybody in the
entire ballpark, and I would say
that the game is not going to start until
somebody has solved it. And somebody, I’m sure,
would solve it pretty quick. I’d be sampling a
wider range of people, and I’d be sampling
far more of them, and I would be
motivating them as well. That’s the thing with mutation. I now want to tell you
what I think is probably the most interesting thing
I know that is not widely appreciated by the public, which
is about the mobility of DNA in bacteria. What do I mean by mobility? I mean that in
bacteria, genes do not stay within a single lineage. They can move from
one to the other. Sometimes they’re on
things called plasmids. Sometimes they can
be moved by viruses. Other times, bacteria
will just take up DNA from their environment,
start making use of it. Which means that rare
traits can spread. So just to illustrate this– if you play a musical
instrument of any kind, can you raise your hand? You don’t have to
play it well, I’m not going to ask you to play it. Quite a lot of people– you
are a sophisticated crowd. Now let’s ascribe
a fitness value to that
musical-instrument-playing. Imagine that we were
only feeding you if you could sing
for your supper, and everybody else would
not be [INAUDIBLE] any food. It would become
a very good thing to be able to play a
musical instrument, and so you guys would
have an advantage. But just imagine if that ability
to do something complicated like playing a
musical instrument could be passed on to
a neighbor by something as simple as shaking hands. Raise your hands now
if you shook hands with somebody who played
a musical instrument. You see? Suddenly that ability
is way more widespread than it was previously. A natural selection has a lot
more to be able to work with. And bacteria do not only
do this within a species– no, they do not. Look at this. This comes from
some work that I did with Dr. Kirby, our second
speaker– he was also on this paper. This shows family trees of
three important bacteria– Enterobacter cloacae,
E. coli, and Klebsiella. These all came from
the Boston area. What you need to know is that
these brightly-colored things link things where exactly
the same gene was found in other, different things. I mean, exactly the same gene. So here you can see that
this– which is a Klebsiella pneumoniae– is also
found in E. coli, which is a different species. To put it into
context, this is as if you were to be
bitten by a spider, and gained the ability
to climb on walls. And bacteria don’t even
need to be radioactive. So– I need to walk over here
to be to remind myself what the next line is now– in closing, I want to
ask the question of– I’ve talked about how
natural selection has worked in the antibiotic era. Does this mean that evolution
has just worked really quickly? Well, no. It’s not so much that. There are so many
antibiotic resistance genes because antibiotics
are everywhere. This, again, is from a piece
of work I was involved in. This is a piece of
permafrost core from Canada, so this is from the tundra. As you dig deeper and deeper
and deeper and deeper, this is stuff that was laid down
longer and longer and longer ago. So bacteria fall
from the atmosphere– where they get carried by
currents, and blah, blah, blah– [INAUDIBLE], and
they get frozen, so you have a deep freeze. And as you go deeper and
deeper and deeper into it, you’re reading back in
time what was living there. We found a gene existing
in Staphylococcus, it looked like, about
6,000 years ago– that was when it was laid
down, that layer within the ice core– that was capable of
conferring resistance to this. This is amikacin. Amikacin is what’s called the
semi-synthetic antibiotic, which has never
existed in nature. It was only developed
in the 1970s. So what was something
doing 6,000 years ago? It’s not that it was
resistant to amikacin– it was resistant to something
that was a bit like amikacin. Remember, Fleming
found the antibiotics as part of a natural processes. These are natural
molecules which have been made in nature for
millions, billions of years. In fact, when I said imagine
a world without antibiotics, there has not been a
world without antibiotics for millions of years. Not since bacteria and fungi
first started their arms race, whenever that was– sorry, I’m not that
kind biologist, I can’t think that
far back in time. There has never been a
world without antibiotics, and so we are continuously
playing catch up. And we and our medical
attempts to prevent the hideous consequences of
bacterial infections are continuously having to
deal with the consequences of this ancient story. So that was my introduction. And I’m now going to hand
over to the first of our three marvelous speakers,
who are going to take us through the topics
which I’ve put up here. And then we’re going
to come back and answer all of your questions. And I want to thank
them for speaking next. I want to thank all of you
for listening, and for coming. Thank you. [APPLAUSE] OK as Dr. Hanage
was just telling us, antibiotics come
from the environment. There’s warfare going
on in the environment between different
microbes that are trying to stake out territory. And there’s limited
resources and food sources, so microbes have
developed the ability to produce antimicrobials–
antibiotics to kill off other organisms in
the environment. And we have co-opted
those antibiotics to use in treating
infectious diseases. And so I wanted to introduce
you to the players. We have us– human cells– and bacteria. A human cell– if
simplistically– is a bunch of protoplasm
surrounded by a cell membrane. And bacteria also are protoplasm
surrounded by cell membrane, but they differ from
us in that they also have a rigid cell wall– shown in gray. And there are some
bacteria, not only do they have protoplasm, a
cell membrane, and a cell wall, but they actually have
a extra cell membrane. So bacteria look a
little bit different than we are, and
those differences can be exploited and targeted
selectively by antibiotics. Now, in terms of
the toughness scale, it’s really easy to
kill human cells. But bacteria have all
these extra layers. It’s kind of hard
to kill bacteria. And it’s really hard to kill
these gram-negative bacteria, because they have all
these different layers. So the trick is to find
things that can kill bacteria, but not us. And microbes produce a
lot of different things. They produce compounds which
can kill human cells too, so we’ve gone and looked
for things that are very selective for bacteria. And those are the things that
we’re using in human therapy. And I just wanted to show
you that antibiotics, in order to get
into bacterial cells and have this very selective
ability to kill bacteria, they turn out to be these
really super weird molecules. So if you look at, for example,
a molecule or a compound that we use to treat human diseases–
not infectious diseases– that just have to get into our
own cells and not bacteria, they tend to be very
simple molecules. The structure’s not important. This is an example of a
common ulcer medication called Nexium, or esomeprazole. This is what a typical
antibiotic would look like. A chemist in his or
her wildest dreams couldn’t think up
this structure. It’s very difficult
to synthesize. But microbes, over millions and
millions of years of evolution, have figured out
just what’s needed to get past bacterial defenses
and kill other organisms. So bacteria, because of the
structure that they have, they have a
fundamental problem– bacteria are surrounded
by a rigid shell. So if you were surrounded
by a rigid shell, and you need to expand and
grow, you have a problem– you can’t really
stretch that shell out. And so the solution
that bacteria have is what I call the
rigid shell paradox– in order to grow, you actually
have to snip that shell. So what the bacteria
do is they snip the shell in multiple
places, and then they stretch out a little bit. And then if they kept on cutting
and stretching the cell wall would fall apart. So what they do is they stitch
the shell back together. So they cut, expand,
sew back together. So now I wanted to introduce
you to our first antibiotic– penicillin– Doctor Hanage
was referring to before. What penicillin does is it binds
to the stitching mechanism, so the bacteria can no longer
sew itself back up together. And so what happens then– and I’ll show you an example. These are bacteria
under a microscope. These are Escherichia
coli, a bacteria that’s found in our guts. And you describe them as
short, rod-shaped organisms. And now if we look
at those organisms and expose them to something
that inhibits the sewing machine, in this case,
a cephalosporin– it’s very similar to penicillin. What happens is the
organism keeps on cutting, and it doesn’t stitch
things back together again. And so the organism
literally falls apart, and it starts to swell up,
and you can see these bulges, and they form these
long filaments. And this is incompatible
with bacterial life, so the bacteria are killed. So that’s an example of how
one major class of antibiotics work. Now, there are a number
of different targets in the bacterial cell,
and I’ll just briefly go through some of them. Some of them attack these
special bacterial membranes that look different than our
own membrane in this cell wall. Penicillin we’ve
just spoken about. And then bacterial
cells, just like we do, have a genetic
blueprint, and there are antibiotics like
fluoroquinolones that prevent replication
of that genetic blueprint. And then that genetic blueprint
sends out instructions into the cell to tell the
cell what it should make, and those instructions
are messenger RNA. And there are antibiotics
that interfere with the production
of messenger RNA, and those instructions
go to the manufacturing centers of the cell, which
are called ribosomes. And those ribosomes make
the structural components of the cells, the
enzymes that carry out various functions in the
cell, and these manufacturing centers– ribosomes. We have ribosomes,
too, in ourselves, but they look very different. Bacterial ribosomes
look very different than our own ribosomes,
so that there are a number of
different antibiotics that selectively
target this machinery. So those are examples of the
major types of antibiotics, and how they can
inhibit bacteria. OK, so I’ll bring
you back to the soil, my environmental slide. And the red bacteria have
been busy killing off the purple bacteria. But as Dr. Hanage was saying
before, evolution is going on, and eventually one of
the purple bacteria figures out a way to
resist that antibiotic. And so there are
several mechanisms by which this can occur. And so, if we go back to
our sewing machine example, we have another molecule
called carbapenem, or meropenem, that can
bind the sewing machine. But now we have an organism
that has acquired or developed a resistance mechanism. So one way to resist
this antibiotic is to break the
antibiotics down. So there is an enzyme which
will cut the antibiotic, and that changes its
shape and function, so they can no longer bind
to the sewing machine. So this organism
is now completely resistant to penicillin. Well, there are a
number of different ways that organisms can become
resistant to antibiotics. Another way is to
not cut the molecule but you can use a
molecular staple to staple a chemical group
onto this antibiotic. And when you do that, the
antibiotic looks different– it has this big bulge
over here, so it can’t find its target anymore. And yet another way is it can
actually change the target itself through some mutations. So the shape of
the sewing machines is different, so, for example,
penicillin can no longer bind. I want to bring you back to
the gram-negative bacteria, these really tough bacteria
that have these two membranes. It turns out that
bacteria also have to get nutrients through
these two membranes too. So in their outer membrane, they
have these pretty large pores, or holes, that are called
porins, so that nutrients can flow into the bacteria itself– until antibiotics can also
flow in through those pores, and then access the cell wall
or get into the cytoplasm. So what bacteria have also
figured out how to do, is they can acquire mutations
in those pores so those poor suddenly become smaller. They’re too small
for the antibiotics to come in, but their nutrients
can get in well enough– maybe not perfectly,
but now the organisms are again resistant
to this antibiotic. And if the antibiotic
still gets in, the organisms have acquired
or developed sort of pumps– they’re called efflux
pumps, and they can pump the antibiotics out. So you can see that there are
multiple, multiple different ways that organisms can become
resistant to antibiotics, and sometimes we find
multiple different mechanisms in the same strain. And as Dr. Hanage was saying,
one of the most remarkable things, as he showed when we
shook hands with each other, is that antibiotic
resistance can be fairly easily transferred
from bacteria to bacteria. And antibiotic resistance
genes are often carried on these autonomously
replicating pieces of DNA– they’re not part of the
bacterial chromosome, they’re these circular pieces
of DNA called plasmids. And often these plasmids encode
multiple antibiotic resistance genes, resistance not to
just a single antibiotic. In the study that Dr.
Hanage was referring to, some of these plasmids
maybe have five or 10 antibiotic resistance genes. And in addition to
encoding resistance genes, they encode a machinery
that allows the plasma to transfer itself, to
replicate, and transfer itself to another bacteria. So this is a
molecular mechanism. It linearizes
itself, and then it forms a plasmid in
an adjacent bacteria. And what’s even worse remarkable
about these plasmids is they often encode an
addiction machinery. So basically, if a
bacteria is foolish enough to try to kick out this
plasmid, the plasmid ends up killing the bacteria. So the plasma encodes
a very stable toxin and an antidote to that toxin,
which is very short-lived. So if the plasmid
happens to be lost, then the toxin hangs around,
the antidote is gone, and the bacteria is killed. So now this purple bacteria
has transferred its resistance to other bacteria. And we have this
poor red bacteria which seem to be doing pretty
well for quite a long time, and so it’s sort of it’s stock. And so now it’s goal is to
acquire some new antibiotic. And what happens, and
what is happening, is a antibiotic arms
race, if you will. And I’m showing you one
class of antibiotics that attacks the bacterial cell
wall– like penicillin that I told you about. And in terms of
human therapy, we’ve started out using
penicillin and ampicillin. Organisms had
developed enzymes that would cut up those antibiotics. And then we went into the
soil, and we pulled out first and second and third
generation cephalosporins, and then the pathogens acquired
enzymes that can now breakdown those resistance mechanisms. When I was in medical
school, we used to think about this wonder
drug called meropenem, or carbapenem, which could
basically kill any bacteria that you could think of. And recently there’s come
into our bacterial populations enzymes that can degrade
these sort of antibiotics of last resort,
called carbapenemases. And so there are these
carbapenem-resistant Enterobacteriaceae. The CDC is calling this
one of our most urgent anti-microbial
resistance threats because they’re resistant
to what was a fairly safe, nontoxic anti-microbial. It had sort of been one of
our last-resort medications against these very difficult to
treat gram-negative organisms. I wanted to bring this
back to our patients. And so, in our patients,
they develop an infection, and we treat them
with antibiotics, and infection’s cured. But during that process– remember, antibiotics don’t
discriminate between pathogens in our normal flora. So our bodies are
covered with bacteria, we have bacteria in our
upper respiratory tract, and in our intestine,
so the antibiotics kill that normal flora too. And in our hospitalized
patients especially, this sets up a vicious
cycle of resistance. So we treat our patients, their
normal flora is knocked out, so then they become
colonized with organisms that are resistant to
the antibiotic we just treated our patients with. And especially in our
hospitalized patients, patients with a compromised
immune system, who might be on chemotherapy,
might have had a transplant, those patients get
infected often from they’re endogenous flora–
they’re colonizing flora. So now they become
infected with a pathogen that’s resistant to the
antibiotic they were just treated with. And then they become colonized
with more resistant bacteria, and this cycle goes
around and around until the patients
may get colonized with an organism such as
Clostridium difficile, which produces a toxin which causes
a very severe colitis, which can be lethal; or
they’re infected with one of those organisms Dr.
Hanage showed an example of, which are either resistant
to all available therapies or effectively resistant
to all therapies, or only toxic
therapeutics remain, and that leads to
adverse outcome. So in summary, antibiotics
and resistance elements are borrowed from an
ongoing bacterial arms race. And bacteria are very
difficult targets, it’s really difficult
for chemists to synthesize new antibiotics. We generally pull them
from the environment, where the bacteria have done
most of the developmental work for us. There are many, many paths
to anti-microbial resistance. We amplify resistance in
our hospitalized patients, so you have to think
about careful use of those antibiotics,
and escalating antibiotic resistance is a looming
societal problem. So with that, I would thank you. And I’d like to introduce
our next speaker, Dr. Farhat. [APPLAUSE] I’m going to talk
to you a little bit about the global impact
of drug resistance. And I’m going to
use specifically one example of one disease– that’s tuberculosis. And many of you haven’t seen a
tuberculosis case in your life, it seems like a
remote disease that affects people
across different seas or really is not a
real problem anymore. But in the next few
minutes I’m going to try to convince you that,
in fact, it’s very much still a big problem
globally, and actually one of the major
types of infections that drug resistance
is hitting the hardest. Back in 1812– so
about 200 years ago– in Massachusetts about
one out of four people died from tuberculosis
infections. Move along to 2017, we barely
have any TB in the US– only about three cases
in 100,000, and almost none of them die. And all of this
thanks to antibiotics. And I think many of you have
used antibiotics in your day to day. TB is a particularly
challenging infection to treat because
you not only have to take one antibiotic
for a week or 10 days, typically you have to take four
or sometimes more antibiotics for as long as six months
in order to get cured, so this is a particularly
big challenge. The fact that we were able
to get this far in the US and Europe and many parts
of the developing world is really a great success
story, and really is a story that we need to protect. And a reality that we need
to protect with everything we have. So in 2017 the latest
statistics from the World Health Organization tell
us that we still have over 10 million
people fall ill with tuberculosis every year. In addition to that,
tuberculosis alone is actually the
top cause of death for any single
infectious organism– more than malaria
and HIV combined. I think, in addition to the
fact that most of these cases are happening
overseas, most of them are in sub-Saharan
Africa, Southeast Asia, particularly India, China. However, our world is no
longer like it used to be– their borders are
not really real. And in fact people
are constantly traveling across the world. And this is really
a reminder that in fact, in 2017, what’s
happening across the world or across the ocean
should be relevant and should be a concern to
us here in the United States. One of the major
challenges that’s really threatening
TB control worldwide is this emergence
of drug resistance. As I mentioned before, treating
regular or drug-sensitive TB infection takes us six months. But treating a
drug-resistant infection can take us as long as two
years, and sometimes longer. This is a map showing
you that in fact drug resistance around the
world is not evenly distributed. It tends to be– so darker here means more cases. And in fact it is
more common in, for example, the former
USSR region, Eastern Europe, and some parts of Africa. But almost every
country in the world has noted and reported
drug-resistant TB cases. And this is a little
diagram to remind us that not only can drug
resistance develop in one person– this is as a result
of evolution, as the previous
speakers had mentioned. When you’re treating
somebody with an antibiotic, and you’re taking the
medicine but then the organism evolves within their
body to develop the drug-resistant
mechanism– so this is the so-called
primary resistance, when you have perhaps they
didn’t absorb the drug, perhaps they missed some
doses, and then they acquired resistance. But increasingly
what we’re seeing is not this acquired
resistance phenomenon. Increasingly people who have
never seen the infection before are getting infected
by others who already have that resistant infection– so
meaning they’re transmitting, these resistant
infections are now being transmitted from
one person to the other. And this is a major
cause of concern. When you have done everything
right, so to speak, you’ve taken your antibiotics,
but just because you are in the wrong place
at the wrong time, you end up getting a
drug-resistant infection. And this is from NPR
a couple of years ago, where in India they’ve
noted the so-called totally drug-resistant TB that
was essentially resistant to a panel of the 13 drugs
that are currently used for TB therapy– which was a major
cause of alarm. And in fact, a
lot of people were saying that this is
threatening to take us back to the era where all
we could do for tuberculosis is put somebody in a
sanatorium and pray. So what is the major
problem with drug resistance in tuberculosis? As I mentioned, it’s
particularly challenging to treat– in the best hands,
it can take up to two years of
fairly toxic therapy. But the reality is, in the
majority of cases of– imagine this is sort of
a sea of patients that all have
multi-drug-resistant TB, which is TB that’s resistant to
rifampicin and isoniazid, two of the most potent drugs
that we use to kill it. The reality is only one out
of two of these patients get diagnosed, that they
eventually get recognized, and they undergo
some kind of testing that proves that they
have drug resistance. And even then, two out of
three people who actually are diagnosed eventually
get access to treatment, because treatment is
expensive and it’s limited. And so a lot of
people don’t actually get treated even
after they recognized to have drug resistance. And even after people
go on treatment, because the treatment is toxic
and because these people tend to be fairly sick, only one
out of two of those patients get cured of their infection. So we’re currently in
this dismal situation of only one out of six
patients with drug-resistant tuberculosis gets cured of their
infection, and five out of six go around potentially spreading
resistance in their communities and really threatening
the public. So this is a diagram from the
Centers for Disease Control, just to demonstrate
how expensive it is and the toll that
it takes to have a drug-resistant infection
relative to having a regular or
drug-sensitive infection. So you can see that these
are estimates from the United States, obviously,
so these numbers are much higher than they would
be say in sub-Saharan Africa. But nevertheless
you get the idea that it costs a lot to
actually treat them– the cost of medicines,
the cost of the physician, the cost of the follow-up. But in addition
to that, the loss of productivity, because
these infections– especially tuberculosis– tends
to affect young people in their prime years of life. So there is considerable
loss of productivity, and in fact it is among the
top causes of bankruptcy or financial ruin worldwide. So why is tuberculosis,
particularly drug-resistant
[INAUDIBLE], particularly challenging to diagnose? The reason is because contrary
to some of the other infections we’re used to, like strep
or a urine infection– things that are more common– TB is a very so-called
slow growing organism. So when you try
to take a sample, say somebody coughs
into a cup, and you try to take that sample to
try to identify whether or not it contains TB, typically
what you’re doing is you’re putting it
on a little Petri dish and you’re watching for
growth of the organism. And in most cases, for
regular infections, it could take about a day or two
or maybe three for the bacteria to grow. But in the case of TB, it could
take two or three weeks for you to recognize that
this is tuberculosis. Most other tests that
we have at the moment are poorly sensitive,
don’t tell you reliably that you have that infection. And then, once you have
the culture telling you that, in fact, you
have TB, you then have to grow it in the presence
and absence of the antibiotic that you’re going
to use for treatment to see if it’s sensitive to–
so similar to– the plate that you saw with
Dr. Hanage earlier, where you had the little
mold and you essentially try to see whether or not
it’s going to grow around that little pill of antibiotic
that you put in there, and essentially try to assess
whether or not it’s sensitive. And so based on
that information, usually clinicians decide
whether or not to give the patient that antibiotic. And again, that
takes several weeks, so you’re talking about a
delay of one to three months– in the case of
tuberculosis– before you’re able to essentially
design a treatment regimen for the
patient that you know they’re going to respond to. So this is obviously
a big problem. So how do you get around this
issue of needing to do culture? As you heard before, drug
resistance is so-called heritable– it’s passed on from one
bacteria to its offspring. Because it’s
heritable, it’s encoded for in the DNA of the organism. And so instead of trying
to grow the organism and test it in a Petri dish,
what you could try to do is you read its DNA and try
to predict ahead of time– identify those mutations that
are causing the resistance, and then make that determination
right then and there without waiting for it to grow. In one particular analysis
we tried to do just that– learn about those
different mutations that are causing resistance
within the tuberculosis strain, within the tuberculosis samples. And so we took samples– this was because TB tends
happened all over the world and it has a fair
bit of diversity, it was important that we sample
from many parts of the world. And so here we worked with
collaborating laboratories across the world
to collect samples, and then we wanted to make sure
that we have a sample that’s balance between samples
that are sensitive and samples that are
resistant so we can make these associations reliably. And then what we
did was we looked at how the DNA was changing. And we compared the different
samples that we got from different sites that we studied,
and essentially constructed a little evolutionary tree–
or like a little life tree– to reconstruct how
the DNA changed across the different
sites, and looked at where DNA changes happened
relative to when resistance was noted. And so this is a little bit of– what we did here
was essentially try to identify DNA changes that
are happening repeatedly when we observe
resistance to happen, and this is one way
we can then make associations between
the DNA changes and the resistance itself. And what we found was actually
similar to what you heard Dr. Kirby present earlier– the antibiotics that we use to
treat TB also target frequently the cell wall, and
so the mycobacteria, or mycobacterial tuberculosis– this is the kind
of bacteria that causes tuberculosis–
has a particularly thick and waxy cell membrane. So it’s actually many
of the antibiotics that we use target
that cell membrane. And then when we try to make
associations with these new DNA changes, we found
that they occurred in genes that had to do with
maintaining the cell wall. So it made sense that we
made those associations, and that, in fact, the cell
wall machinery was changing in response to drug resistance. And knowing that information
allowed us to essentially then move on to construct a
model that would take in all the genetic or DNA
information, and then would allow us to essentially
make predictions about whether or not a particular
strain was in fact sensitive to the antibiotics. And we could do that for each
of the individual antibiotics that we studied. So this was essentially
the results here that we could make
very good predictions for some of the drugs
here in green, not so good for some of the
other drugs here in kind of a darker orange. And when we looked at the
number of different mutations that we found, we found really
an inordinate number, really a large number of
mutations that need to be identified for us
to make good predictions, directly, without
needing to do culture. And so we are
following that up using essentially additional samples,
a larger number of samples to try to get the performance
of our predictions to a level that we could use
for patient care. And in addition to this,
because we are working with tuberculosis– which is in
general has limited research funding, because it tends
to affect relatively poorer nations– we needed to all of the
results of our analyzes out there so people can use
them, and make predictions, and improve upon them. So we designed a
web platform that would allow people to
input their data and output a prediction of
their resistance. And this is a little bit of
what the prediction would look like– it would give
you a little heat map here, with more red
indicating a higher probability of resistance. It also gives you an estimate
of what the error involves, and you can also hone in
exactly on the details as to what mutations
actually led to that estimate of resistance. So then you might say– OK, but how would you
actually translate those, that knowledge,
and those models to actually being able
to take care of patients? How would you use that
in a diagnostic way? So I just want to talk
a little bit about some of these tasks that are
currently used for patient care or are currently in
development for patient care. This is called the GeneXpert
test, which is currently FDA approved, and
is used actually pretty widely across the world. And what it does is essentially
you take in a lung sample from a patient, you essentially
do very minimal processing of that sample, you put it
into this little blue cartridge here, and then essentially
put it into this machine. And what that machine
does, it essentially looks for certain genetic
mutations in the bacteria. And right now it only looks
for a very small number of mutations that
specifically have to do with one type of
drug resistance called– the drug rifampicin, but the
hope is that we would then, on the next phase of this– and
the company’s developing such tools– would allow you to detect
resistance to a larger number of antibiotics. Because that’s
actually necessary given the fact that
we usually treat tuberculosis with
four or more drugs. But in addition to that,
there are these other, more promising technologies
that not only detect one or two mutations but
also detect hundreds of them. These so-called
arrays, where you have essentially multiple
little spots that have different
kinds of probes that light up or give a different
signal when they identify certain mutations. So these are arrays-based
technologies. And the wonderful
thing about these tools is that you can get a sample to
answer within about two hours. So they can really
be used almost at the patient’s bedside, the
so-called point-of-care test. And in addition to that,
these usually cost under $5 a test, which is
really incredible. But increasingly, as
I mentioned before, we found hundreds of mutations
that are encoding resistance in tuberculosis. And so it is more than
likely that the capacity of these tests is
going to be limited, and they won’t necessarily be
able to detect the entire span of relevant mutations. In fact, what we
might end up doing is kind of like a
sequencing-based test, where essentially you get
a sample from a patient, and essentially be
able to read off the entire genome
of the bacteria. And increasingly
there are technologies being developed
worldwide that would allow us to do that closer
to the patient in a very cheap manner that would also
produce high-accuracy results. So one example of this tool is
the so-called USB sequencer. So it’s this little machine,
sort of as big as your finger, and is able to
generate a whole genome sequence within a few hours. So this is a little bit of a
sense of what’s coming down. This is definitely not
currently used for patient care but we are optimistic that
these kinds of technologies are really going to change
the way we diagnose drug resistance, and that’s going
to be in fact necessary for us to shorten that time from
when the patient comes in, for when we put them
on appropriate therapy. So you can see that, relative to
the current delays of about one to three months, if you have a
sequencing-based technology– was it an array-based or the
GeneXpert test or the whole genome sequencing-type
technology– that it would take
us less than a day. Hopefully when the patient is
right there in front of you, you’d be able to make
that determination, and then decide right away
what the appropriate treatment regimen would involve. And that’s it. So thank you so
much for listening. [APPLAUSE] I’d like to introduce
next Dr. Michael Gilmore. [INAUDIBLE] [APPLAUSE] Thank you. That’s a lot of science
to wrap your head around– even if you’re in the business. It’s a pleasure
to be here today, especially in Boston
because Boston has been central to the
development of antibiotics and is, I think, going to
play a very central role in addressing the antibiotic
resistance problem. Remember that person
whose hand you shook at the beginning of this? There’s a 90%
chance that they’re carrying a
penicillin-resistant Staph aureus In the hospital, when
you go in, they’ll take a swab and whirl it once
around your nose, and you’ll be
tested for something called methicillin-resistant
Staph aureus. And about one
third of the people are positive for that Staph. But that’s just one
trip around the nose. If you swab the other nooks
and crannies of everybody else, you’ll find a Staph, I guarantee
you everybody has a Staph. And 90% of Staph now are
penicillin-resistant. About a third are also
methicillin-resistant. So antibiotic resistance
is real, it’s here, and it’s on you. And I hope that’s the
worse that you have. Most of that we
can still handle, but it gets much, much worse. As Dr. Hanage pointed
out, there are strains now that are pan-resistant
to everything. And also, as you
heard with the TB, those are becoming extremely
antibiotic-resistant as well. So it’s a real problem. Let me take you back in time
before antibiotic resistance was a problem. How far back do we have to go
before antibiotic resistance was a problem? We have to go back to before
the human use of antibiotics. So let me take you
back to Boston in 1942. Was anyone in Boston in 1942? A few, not many, but
maybe one or two. And, in particular, let me
take you to November of 1942. And what do you imagine– or what might you remember– was going on back then? Yeah, the US had been in World
War II for about 11 months. Remember, December 7, 1941,
was Pearl Harbor, and then– so this is about 11
months after that. So the US was really
getting involved in the war, a lot of soldiers were
going over to Europe. Does anybody know who the
number one football team in the country was in 1942? Boston College. And Boston College, November
28, played Holy Cross, and they were expected to just
wipe the field with Holy Cross and then go on to the Sugar Bowl
and be the national champion. But Holy Cross’s defensive
coach changed the plan, and really confused
BC, and Holy Cross ended up winning 55 to 12. And knocked BC out
of the Sugar Bowl. So a lot of revelers went to a
place called the Coconut Grove. Has anybody heard of
the Coconut Grove? Yeah, if you’re from
Boston, there’s– and if you’re from Boston
from until about 1960, after that a lot of people
may not know about it. But the Coconut Grove was
a very popular nightclub and it was able to
handle about 600 people. It was a pretty big place. It had several bars and a
dance floor and other things. But this night in November
there were 1,000 people there celebrating– soldiers,
revelers from the BC-Holy Cross game– in fact, BC planned
to have a party there, but ultimately didn’t
when they lost. But the reason I point that out
is because there was a fire. And it was a huge tragedy. Ultimately just under 500
people were killed in this fire. The fire was a big
event for Boston. It was the biggest
fire since a fire that happened in Chicago in
something like 1903, or something like that. So the biggest
fire in 50 years– and I think probably
the biggest fire ever since, because ever
since then, they’ve changed the building codes. One of the reasons
so many people died– obviously there were
many more people than the place
could accommodate. As I said, it was
approved for about 600 but there was near 1,000 there. It didn’t have many exits. In fact it only had one exit–
that was a revolving door. And when you have a fire,
that’s obviously not an efficient way to get
people out of the building. So a lot of people were trapped
inside, and a lot of people died. So that night the injured,
those that were burned but still clinging to life, were taken
to the Boston area hospitals. And, as you know, we’ve–
got some of the best. So 114 people clinging to life
were taken to Mass General, and within the first two
hours all but 39 were dead. So 39 were taken care
of at Mass General. Now, in World War II
it wasn’t well known, but penicillin was being
developed for the war effort because, in wars, more people
die from infections than they die from the injuries. In fact in the Civil
War, 2/3 of the people died from infections. So Dr. Florey– who Dr.
Hanage mentioned– came over, and England– afford– because they were
in the middle of holding back the Germans– couldn’t afford to
develop penicillin. So Dr. Florey came
over and made the case to President Roosevelt
and the Defense Department to invest in developing
penicillin– which they did. And some of our investigators
and physicians at Mass General were involved in this top secret
development of penicillin, and studying how
to use penicillin to treat war injuries. So that night in
November of 1942, recognizing that most
of these 39 people who made it that far
were likely to die from their injuries,
the physicians and scientists involved
in that research contacted Merck in Rahway
New Jersey, and said, we need all of the
penicillin that you’ve got. Back then there
wasn’t much, in fact, so Merck sent all
of its penicillin– and it wasn’t even
purified penicillin, it was just the culture fluids
from trying the first steps of making penicillin. So they brought big vats
of these culture fluids. It was a seven hour
drive, they had police escorts the
whole way, and they were able to save a
remarkable number of lives. So the first public
use of an antibiotic happened in Boston
with the Coconut Grove. So that was the start of it. Now, at that time
effectively 0% of people Staph aureus were
penicillin-resistant, and Staph aureus is a main
cause of infection after burns. So that solution
wouldn’t work now. We could try, but
it wouldn’t work. In fact, had we tried
it as recently as 1960, it wouldn’t have worked. So antibiotic
resistance– resistance in Staph to penicillin rose
from nothing to about 90% by about 1960. That’s how it works. So antibiotics are sort of like
where Darwin meets Newton– for every action that
we make biologically with an antibiotic, nature has
an equal and opposite reaction. That’s the way it works. So let me just take you
through a couple of things. So this is a little bit more. It turns out a
waiter’s match seems to be what started the fire–
although that’s still being debated in historical circles. You can see this is
what it looked like, and it was said that that match
started some of the paper mache palm tree-like decorations,
and it went up flames. The roof was covered in–
that’s actually a blue cloth, so there was a lot of
flammable material, things that now there are
building codes that we learned from this very fire. So when you see building codes,
it’s largely because of this. Does anybody live in
the Bay Village area? That’s where Coconut Grove was. It’s just over–
if you know where the public garden is,
it’s about two blocks toward the south end. So there’s still a monument
there in the sidewalk where the Coconut Grove was. So that’s how antibiotics work. Before going
forward, let me just say that there are some
terrific physicians and scientists in
the Boston area who have been integral
in this problem ever since those
Mass General days, and I’ll touch on
a couple of those. But one of the reasons
that we have this problem is that antibiotics aren’t
just used to treat patients. In fact, 2/3 of the antibiotics
that are made in the US– or 3/4– are given to animals. And the reason they’re
given to animals, mainly, is to promote weight gain. So when you have high capacity
animal production facilities, animals don’t react well
to that, and often get sick and are weakened
because of the crowding, and they’re in close proximity
to each other and passing things around. And so people found long
ago that if you gave animals some antibiotics
in their feed, you could keep that
down a little bit and they’d gain weight faster. So that’s what we do. Only about a quarter are used
for humans, and only about half of what you use for
humans are actually used in a way that’s
really useful. So we’re squandering this
resource– that’s the problem. So as I mentioned at the outset,
for every pressure we put on bacteria, they push back. The bigger the
pressure, the harder they’re going to push back. So by not being
judicious in what we do, we now are confronted
with this problem. Well, why are we feeding
antibiotics to animals? While we’re doing that
mainly because antibiotics are made by companies. And companies exist,
really, to make money. And I don’t fault
them for that– that’s why a company exists. You start a company
to make a product and to sell the product. If you can sell more of the
product, you have more sales. And if you have more sales,
you have more revenue. So you have an incentive
to find more uses for these antibiotics. As long as we were
discovering new antibiotics we didn’t really have to
worry about the consequences. We could discover a
new one in a few years, and then it really wouldn’t
be that big of a problem if resistance developed. At least that’s how we
used to think about it. Antibiotics, on average,
have a life span of about five or eight
years before resistance becomes a real problem– just like penicillin and
Staph, something like that. So if we can develop an
antibiotic every five or eight years, we’re OK, we just
have to keep doing that. The problem is we’re
not doing that anymore. And that’s– let me show you. I skipped over– or
maybe it’s not in there. 1928 when we first
came across penicillin until about the
1960s, we were doing that, we were discovering
a new antibiotic every five years or so. Since 1980, we haven’t
really discovered much in the way of new
antibiotics at all. We’ve introduced a few new
ones, but they were ones that we knew about before that
were simply put on the shelf because they didn’t look that
attractive for development. We really haven’t approved any
new classes of antibiotics. We’ve developed a lot of
antibiotics that are modified versions of old antibiotics. So you saw second, third, fourth
generations of cephalosporins, you see a lot of
tetracycline derivatives, you see a lot of different
modified types of antibiotics– but they’re all the same class. The problem with that is,
once you have resistance, it’s a much smaller step to
resistance to the new class. So we’re not developing
any new compounds for which we haven’t
already groomed the soil for resistance. One of the big problems in using
antibiotics in animal feed, and indiscriminately, is
that what we’re doing, they’re doing in the
developing world– and in some very large,
very populous countries, like China and India– about 10 times what we’re doing. So what we’ve contributed
to resistance, they’re now engaged in the same
kind of practices that we used. And unfortunately we don’t
have the moral high ground to ask for restraint, because we
haven’t set a very good example in that regard. So we haven’t been very prudent
in the way that we’ve used it. So who’s going to
solve this problem? As I said at the
outset, Boston’s a very good place to be if you
want to be part of the team to solve the problem. And you’ve seen the
three previous speakers– they’re all leaders
in the field, and deeply engaged in coming
up with solutions to this. I’ll just walk you
through a few of them. We’ve got the Boston Area
Antibiotic Resistance Network– that’s a working group of people
from academics and industry who get together once a year. They’re all in the
Boston/Cambridge area. Within Boston and
Cambridge we have over 50% of the
world’s experts– or of the US experts, any
way– working in this area. And so we can get together,
and exchange ideas, and find ways to
interact and collaborate. And so we do that, and we
meet once a year to do that. One of the things
that I’m running is called the
Harvard-wide Program on Antibiotic Resistance. It’s a group of investigators
from around the Harvard environment, including
Mass General, Mass Eye and Ear Infirmary, the med
school, the Cambridge campus. And we’re working
on the problem. There’s another Harvard-wide
group called the Microbial Sciences Initiative. These are all leaders– Bill is at the Harvard
School of Public Health, and leading efforts along with
Marc Lipsitch at that school– and are deeply involved
in looking for solutions. Also, we have a gentleman named
Stuart Levy over at Tufts. And Stu, I think, has
to be acknowledged in any talk on the subject
of antibiotic resistance. He really championed
this from the late ’60s and has been pushing the case. He started an organization
called the Alliance for the Prudent
Use of Antibiotics. So we have a terrific nucleus. Some of these efforts are
starting to spin out companies. A Harvard scientist named
Andy Myers, a chemist, developed new ways to
make tetracyclines, and new ways to make
another class of antibiotics called macrolides. Macrolides include erythromycin,
azithromycin– drugs that you might have taken. And so there are two companies
based on his technology. There’s a woman named
Lori [INAUDIBLE], who’s looking at ways of killing
a microbe called pseudomonas. And a company called
Spero has started around her technologies. Another innovator
in the field is a guy at Northeastern
named Kim Lewis, and he’s identified some very
intriguing new antibiotics and has started a company
called NovaBiotics. So a lot of this effort is going
in very practical directions to come up with new
antibiotics that we’re in sore need of at this point. So what can you do? Let me just give you some
practical advice if you’re worried about antibiotics– if you have an infection
and go to the doctor, ask them [AUDIO OUT]
they could culture it. A lot of antibiotic use
is given empirically, without actually testing to see
that this antibiotic will work. Whenever you can press for it
to make sure the antibiotic is useful for whatever is causing
your infection, ask for that. If there are reasons that they
can’t do it, they’ll tell you. But it’s worth asking. And don’t ask for an antibiotic
if the doctor says– well, I’d rather not give you one
for what you’ve got right now. Because a lot of sore
throats, a lot of sinusitis, a lot of other things
are not bacterial, they’re caused by viruses,
and a antibiotic will only attract antibiotic-resistant
microbes to you, so the next time you
get an infection, it’s more likely
to be untreatable with that antibiotic. You don’t want that. Anti-microbial
hand soaps– that’s something that a lot
of people talk about. Well, it’s really
unnecessary in daily life, unless you’re taking care of a
sick child or something who has something that you don’t want
to spread around to the rest of the family–
that’s reasonable– or if you’re handling
something like raw chicken. We worked with Consumer
Reports, and found that 75% of chicken meat
from grocery store shelves– and they had a very
nice article about this in Consumer Reports– had
antibiotic-resistant bacteria on it. So if you’re handling those
things in the kitchen, an anti-microbial soap is
not a terrible idea for that. Or– you’ve heard about
MRSA infections in gyms, methicillin-resistant
Staph infections in gyms– those have become sort of
a point of transmission. So it’s not unreasonable to
use an anti-microbial soap and washing your
hands after that. What can you do to limit
the economic incentive for feeding antibiotics
to cattle and chickens? Well, you can buy
antibiotic-free meat. Might cost you a little
bit more but that’s the responsible thing to do. That’s what we all
should be doing– paying a little
bit more for meat, and keeping the antibiotics
for treating the infections that we get. You’re going to pay
one way or the other. And either you’re going to pay
with an antibiotic-resistant infection or you’re going
to pay a few dollars more for the meat, so I’d
suggest buying the meat. Fish– farmed fish. People are dumping
antibiotics into water, into the ocean and lakes,
when they’re farming fish. And that’s just basically
breeding antibiotic resistance. We don’t want that. I’d suggest avoiding
it if you can. And then, finally– do
what you can, if you can, to support research, training,
idea exchanges like this. If you are associated with a
foundation or a company that’s looking for a cause, this–
as Dr. Hanage pointed out– is really one of the most
pressing public health problems that we have, and it’s
only going to get worse. And so elevate the
consciousness of your coworkers about this problem, people
who might be in a position to contribute to it. So, with that, I hope
all of you escape antibiotic-resistant infections
for as long as we all can. And, with that, thank
you for your attention. [APPLAUSE] And, if you would,
give Dr. Hanage another round of applause for
his organizational efforts. [APPLAUSE] And I’ll turn it over to
Bill to manage the questions. Thank you very, very,
very much, Mike, indeed. And a round of applause for
all of the other speakers. [APPLAUSE] And now your hands are tired
from all that clapping, I’d like to invite the speakers
to come and sit here in front. Now, we don’t have a huge
amount of time for questions, so I’m going to take them in
roughly the order in which they were handed to me, because
some of them are really good, and the first one,
I think, is a doozy. It is, could you
use bacteriophages instead of antibiotics? Now, for those of you who– we may get this– don’t know, bacteriophages
are the viruses that prey upon bacteria. They very effectively
kill bacteria. So presumably, if bacteria
are making you sick, we should be able to give a
virus which kills the bacteria and not you, and use
as a therapeutic. So I would like to hand that
first of all to Dr. Kirby, would you like to
speak to that question? Yeah, absolutely. So this is something that’s
in development right now. Bacteriophages tend to be very
specific for certain bacteria and specific for certain
bacterial strains, so I think what
people have found is they have to do a lot
of developmental effort and you may need multiple
phages to make sure that you can effectively
kill a bacterial pathogen. But there’s some
evidence in animal models that this actually
can work, and I believe there’s even some
anecdotal evidence in humans suggesting that this
may have some promise. Because it was a
friend of mine at Yale called Paul Turner, who
earlier this year was able to use a bacteriophage
isolated from a lake somewhere in Connecticut to
treat successfully an abscess from a patient
that was otherwise refractory to treatment with
conventional antibiotics. I think that– Mike would you like to add? Well, I would say in Boston– has anybody heard of Aerosmith? [LAUGHTER] Has anybody read Sinclair
Lewis’s Arrowsmith from about 1924 or something like that? Phages were thought,
back in the 1920s, to be the magic bullet
that we could use. And in fact they were
developed for that purpose. And there’s an institute
in Tbilisi, Georgia, called the Eliava Institute that never
got on the antibiotic train, and continued to
work with phages. I think we got super
enthusiastic about antibiotics. I think there’s this
whole world of phages that we should probably
go back to and take a good hard look at. I think it has [INAUDIBLE] Dr. Farhat? I don’t have much to add
on that, but, yes, I agree. I think that the key
here is to really be thinking outside of
the box, towards therapies that are completely different. So one other thought
that’s come up on this question of
potentially treating infections without the use of
antibiotics as potentially therapies that one
could use to boost the host’s immune system–
or the human immune system– in some cases. And in the case of TB there
are some such therapies that are currently
being investigated. And in addition to
that, there are also some thoughts about potentially
using even different bacteria. I mean the question
is whether or not we can somehow out-compete
the bacteria in our own body, and whether or not
something like a probiotic would be helpful. This is an interesting idea– very much an idea still– but these are some
thoughts that are coming up that are trying to
challenge the more traditional use of
antibiotics given in emerging drugs resistance. I mean, just to add a
little fat and lead us into the next
question, a colleague of Maha’s was apparently going
through British immigration earlier today and was asked
what he was doing there. And he said, I’m giving a talk
about antibiotic resistance. And the guy on the
boarder said, really? Why don’t you use
bacteriophages? Which was quite impressive. But one of the answers that
he was thinking about giving is that they’re very
strain-specific. Think about natural
selection– we have very good immune
systems in order to throw off the
things which infect us. Bacteria are very good at
avoiding bacteriophages– it’s a very strong
selective pressure for that. And so every virus
is typically only good at fighting or killing one
particular strain of bacteria. And if you don’t know what
you have, then it’s a guess. Which leads us into
the next question, which is about empiric– or best-guess– treatment. As several people mentioned,
when we’re treating disease, we often make a guess
as to what’s there, and so we take what’s like
a broad spectrum antibiotic. And boiling down the
question, could there be a sort of comment on
the sensitivity slash specificity of such guesses? Do you have anything to
say about the practice of broad spectrum
therapies as opposed to more targeted things? And I think I’ll leave
that to you, Maha. Sure. So I think that
it would obviously depend on the kind of
infection you’re talking about. So there are a lot
that we know about the so-called epidemiology–
meaning the kinds of infections that cause certain symptoms. We don’t know very much, given
that each type of bacteria has been found to have a range
of sensitive to resistant, whether or not that
particular, say, bacteria is going to
be in fact resistant. So we have– I guess
is what I’m saying is that you have some idea,
but you’re not definite about the range of infections. For example, in the
case of strep throat, strep throat is almost
universally going to be penicillin-sensitive,
so you can reliably treat with a very narrow
spectrum antibiotic. But for certain other
infections– like pneumonia, say– there’s really a variety
of different infections that you use. We are often treating
so-called empirically. And the success rate of
broad spectrum antibiotics– for the most part–
is very high. But I think, increasingly,
we’re seeing that even in some cases– again, it’s currently
thankfully rare– that they fail these broad
spectrum antibiotics. I think ideally– which just
sort of goes back to Dr. Gilmore’s recommendation– when
you can get more information about what the infection is– meaning through
culture, if you can– that would be ideal, because
that would identify exactly the infection that
you have, and it would allow the further
testing on whether or not it’s sensitive to antibiotics. And you would be, essentially,
not driving blind, hoping for the best. Anybody want to add to that? I’m slightly surprised you
didn’t mention genomes and DNA, because if you could use
DNA to identify what we’re susceptible or resistant to– problem solved. Anybody? Go ahead, James. Sure. So if you have a bloodstream
infection, for example, with an organism which
was mentioned before– pseudomonas– every 24 hour delay in getting
patients on the right therapy confers about a 10%
increase in mortality. So the stakes are high
and with emergence of anti-microbial
resistance, our guess is, for empiric therapy, even
if we get broad spectrum, may be wrong. So I think it underlies our need
to have more rapid diagnostics so we can figure out very
quickly, because there’s so many different
possibilities now in terms of what might be remaining. So we need to figure
out very quickly and have the diagnostics
that can tell us as soon as possible what an
organism is susceptible to. I would just add that we use– clinically– what we have. And we have broad spectrum
drugs, most of which can be taken orally. And the reason we have
those is because those are drugs that could be
used for the greatest spectrum of conditions. So if you’re a company,
again, making a drug, that’s what you want. You want to be able to get a
lot of it out there, and do it. If you have a very
narrowly focused drug, you’re only going to
sell a little bit of it to just those
people and it’s not going to work for a
lot of other things. We really need
broad spectrum drugs that work because in
the first minute– as James said– we don’t know
precisely what’s causing it, but we want stop it
as quickly as we can. Because every minute
that you don’t treat a serious infection,
mortality goes up. So you want to give a drug
that will work before you even have information. So broad spectrum drugs are
really important for that. But, again, we should
use them very sparingly. I would have to say, when
you cross the 50-year-old age level, all of a sudden you
get covered for a visit to a periodontist. And so your dentist
almost always will refer you to a periodontist
because now it’s paid for. And I don’t mean to malign
any practice of medicine, but I was advised to
take two antibiotics– metronidazole and
ciprofloxacin– for a condition
that’s not very severe and that I’m not
really sure that I had. And that really is a profound
dose of antibiotics to anybody. And I would say that should
only be reserved for the worst infections that I might
have, but that’s not what’s happening in practice. So I think we need to heighten
people’s awareness that– OK, if I don’t really need
antibiotics that badly, I shouldn’t take them. That was an excellent
point, which I would echo. Unfortunately, we are
running out of time and I can see some
people are unfortunately having to shuffle
out the back already. So in the interest of that,
I have one more question, which I think might
be directed at Mike, but I’d like to get
answers from everybody. Crisply, please. What’s bad about
anti-microbial soap? [LAUGHTER] I would just very
quickly say that we need the normal
bacteria on our skin. We need the normal bacteria in
our guts for our own health. When we remove the
bacteria on our skin with anti-microbial
soap, then that opens the door to ones
that aren’t as benign. So it’s those benign bacteria
that we carry around in health that we need to preserve. Better the
Staphylococcus you know. Yeah, that’s exactly right. Does anybody else have
anything to add to that? OK, in which case,
and all that remains me is to thank Dr. Gilmore,
Dr. Kirby, Dr. Farhat. I want to thank all of you. I want to thank
Belinda and Susan, who managed to organize this. And thanks all for coming. Sorry if I didn’t
get to your question.

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