0:01

Hi.

0:01

I'm Stephanie Strappie. People call me Steph.

0:04

I'm the Associate Dean of Global Health Sciences

0:06

at the University of California, San Diego, and

0:08

I now co direct the new Center for Innovative

0:11

Page Applications in Therapeutics known

0:13

as iPath. That's the first page

0:15

therapy center in North America.

0:18

But that's the end of the story. You want to

0:20

hear how I got there, right, Well,

0:22

it's a crazy story. People often don't

0:24

even believe that it's true,

0:27

but it really is. My husband

0:29

and I went on vacasion in Egypt

0:31

in the fall of twenty fifteen,

0:34

and we're scientists. We travel

0:36

together and we always do

0:39

off the beaten path kinds of things. We

0:42

had a dream of, you know, going to see King

0:44

Tut's tomb, and we floated down

0:46

the Nile River in a wonderful

0:49

ship. So everything went great

0:51

until the night before we were supposed to see

0:53

King Tut's tomb, and Tom

0:56

and I had this wonderful meal on top of a cruise

0:58

ship and he got violently

1:00

all afterwards. I mean he was throwing up all

1:03

over the place, and you know, I just thought

1:05

he had a bad muscle or something. Like that,

1:07

but actually he got very sick. We had

1:09

to call a doctor to the ship. The doctor

1:11

said, he's going into shock. There

1:14

was no hospital in Luxor, where

1:16

the ship was docked, so we ended

1:18

up having to go to a community clinic there.

1:21

They diagnosed him with pancreatitis, which

1:23

is essentially an inflammation of the pancreas.

1:26

But when I called back home to our colleagues

1:28

who are leading the Department

1:30

of Infectious Diseases at UC San

1:32

Diego, they said, hey, that's just a symptom

1:34

of something else. Because you know you're

1:37

the wine drinker in the family. Tom

1:39

doesn't drink nearly as much as you, and that's

1:42

usually one of the causes of pancreatitis.

1:45

They said, something else is going on. And

1:48

luckily we had travel insurance, so we

1:50

were able to get him medevact

1:53

to Frankfurt, Germany, because

1:55

he was too sick to be metavact home.

1:58

And there they did a sea tea

2:00

scan and saw that he had a giant abscess

2:02

in his abdomen, the size of a football. And

2:05

the doctors came to me and said, you know, there's

2:08

something lurking inside this abscess,

2:10

and they showed me this putrid flask

2:13

of fluid that they'd taken

2:15

from this abscess, and they said, something's

2:17

growing in there, and we have had to

2:19

culture it. It's going to take a couple of days.

2:21

But let's hope it's a garden variety of microorganism

2:24

because there's a lot of multi drug resistant

2:26

bacteria in Egypt. Well,

2:28

I was getting a little bit worried, but you know, I thought,

2:30

hey, we have antibiotics. Anything you know

2:32

that's grown in there, we can handle it. Well,

2:35

the doctors came back in a couple of days and

2:37

they showed me that this

2:40

name of this organism was ascimeo

2:42

bactor bomanii, and it's

2:46

something that I used to plate on my petri

2:48

dishes back in the nineteen eighties when I was

2:50

taking a rusty old degree in microbiology

2:52

at the University of Toronto. And again

2:55

I really wasn't that worried, but they said, look,

2:57

this is actually the worst bacteria on the planet.

3:00

I thought, you know what, how can this be the worst

3:02

back here on the planet, because, like you know, twenty years

3:04

ago, we just had to use like goggles

3:06

in a lab code and that

3:08

was it. It was not worrisome at all. Well,

3:11

it turns out that the antime chrobia resistance

3:13

crisis had crept up on us, and

3:15

Tom was essentially the poster child

3:17

for this post antibiotic era that we've

3:19

entered now. And so the

3:22

doctors did what's called an antibiogram

3:24

to find out the antibiotics that could

3:26

be used to hopefully treat this thing. And

3:28

they came back and they were even more alarmed because

3:31

there was only a couple of antibiotics

3:33

that it was partially sensitive to,

3:36

and it was resistant to fifteen right

3:38

off the top. Well, I started

3:40

to get worried now, and this

3:42

is right before Christmas of twenty

3:45

fifteen. Luckily, they stabilized

3:47

him, got him sent back to San Diego,

3:49

where my colleagues in the Department of Medicine

3:52

were looking after him. And I thought, okay,

3:54

we're fine, we're home now, right, everything's

3:56

going to be fine. We'll find some antibiotics to, you

3:59

know, to cock tol together to cure this

4:01

thing. And they repeated the

4:03

culture and they found out that now,

4:05

and even though only a few weeks had passed, this

4:08

organism was resistant to all antibiotics,

4:10

I mean, even the last resor antibioticaliston

4:13

that was developed in world War two.

4:16

Well, they said, you know, he's too weak

4:18

for surgery. We have no choice

4:20

but to use interventional

4:23

radiology to essentially stick

4:25

the holes in his abdomen and put these

4:27

catheters in there to try to drain out this

4:29

infected fluid out of the abscess and hopefully

4:31

it would shrink and then he'd be better. Right,

4:34

Well, not so fast, because even

4:37

though he had started to improve, one

4:39

day, he sat up in bed and

4:42

this tube inside his abdomen

4:45

slipped and it just dumped

4:47

all that infected fluid into his abdomen

4:49

into his bloodstream, and immediately

4:52

he went into septic shock right in front

4:54

of my eyes. And I'm telling you, it was one of the scariest

4:56

moments of my life. We were actually supposed

4:59

to get discharged in a cute care facility

5:01

the next day, but that wasn't happening anytime

5:03

past. In fact, he was rushed back

5:06

to the ICU in the same hospital

5:08

and put it into an induced coma

5:11

for a couple of days to give his body

5:13

to rest. And he did wake

5:15

up from that, but now this organism

5:18

is now in his whole body. He was

5:20

like fully, like systemically

5:23

infected, and from

5:25

that moment on. He was dying a little

5:27

bit more each day, and

5:29

it was just horrible to watch. He lost one

5:31

hundred pounds off of his frame. He

5:34

was in and out of a real coma that he wasn't waking

5:36

up from. And one day I heard some

5:38

colleagues on a conference call when I

5:40

was trying to, you know, keep one tether

5:42

back to the real world, and

5:44

they said, does anybody realize that you

5:47

know there's anything? Told step that her husband

5:49

is going to die? And I thought, oh

5:51

my god, like nobody has. And

5:53

I cradled the phone in my arms

5:56

like a baby, and I thought they

5:59

just didn't want to tell me, and I'm going to lose

6:01

them unless I do something. So I

6:03

had this conversation with Tom and asked

6:05

him if he wanted to live. And I

6:08

didn't know if he could even hear me, but I said, if you

6:10

want to live, please squeeze my hand and I'll leave

6:12

no stone unturned. And he

6:14

squeezed my hand. Now, I

6:17

mean, I was thrilled, but I thought,

6:19

you know what am I going to do? Like I'm not a medical

6:21

doctor. I don't know how to cure

6:23

this thing. But I did what anybody would

6:25

do in my shoes. Because I'm a scientist. I

6:28

went home and I hit PubMed, you

6:30

know the Google scholar for scientists that the National

6:32

Library of Medicine has developed, and I found

6:34

this ancient, one hundred year old therapy called

6:37

phage therapy, which are essentially

6:39

these bacteria. Phages are

6:41

viruses that have naturally evolved to attack

6:44

bacteria. And I had heard about them

6:46

in my microbiology classes way back in the nineteen

6:48

eighties, but I never knew that they've been used to treat

6:50

bacterial infections. Well turned out

6:52

that they had, that they were considered experimental

6:55

treatment in the West, and they're only

6:57

being used in the former Soviet Union and in

6:59

parts of Eastern Europe.

7:02

So I asked the colleagues that were treating

7:04

TOM. I said, you know, could we use phage therapy

7:07

to treat tom and that lead

7:09

infectious disease Doctor doctor Chip

7:11

Schooley, who is a close colleague of mine, he said,

7:13

what an interesting and intriguing idea. You

7:16

know, if you could find phages that matched

7:18

a Tom's bacterial isolate, I'll

7:20

call the FDA and request compassionate

7:23

use permission for us to use

7:25

phage therapy to cure them. But I've

7:27

never done this before, and I don't know anybody

7:29

who has, so you know it's a

7:31

long shot. Anyway, long story

7:34

short, global village of researchers

7:36

from all over the world stepped up, including

7:39

researchers from Texas A and M University,

7:42

San Diego State University, and even

7:44

the US maybe chipped

7:47

in, and we found phages in the nick of time

7:49

to match Tom's bacteria,

7:52

and we injected them into his

7:54

body, a billion phages per

7:56

dose every two hours. We didn't know if

7:58

we were going to kill him or cure. But

8:00

three days later he lifted his head

8:02

off the pillow and kissed his daughter's hand,

8:05

and I'm telling you, it was the happiest day of

8:07

my life. So that's our crazy

8:09

story. I left a lot of it out, but it's

8:11

in our book, The Perfect Predator. If you want

8:13

to hear more details, you want to say, Hi Tom,

8:16

Hi Tom, how

8:19

are you feeling these days?

8:21

I'm feeling great.

8:22

Can't complain.

8:23

Well I could, but nobody's going to listen after

8:26

it. I got saved like this, Well it's

8:28

better than the alternative, right, You're damn right.

9:16

That was amazing. Thank

9:19

you so much, Stephanie. We really appreciate

9:21

you taking the time to come on the

9:23

podcast and share your story with us.

9:26

We really really do. It's oh

9:28

man, what a

9:31

bonkers story.

9:33

I really really and we'll

9:35

mention this again, but I really really encourage

9:38

everyone to go out there and read The Perfect

9:40

Predator, which is the book that she wrote

9:42

about this experience. It was on

9:45

put downable. If that's a word, I

9:48

could not put it down. How about that.

9:51

I really hope that that's a word.

9:53

Yeah, I don't think it is.

9:55

Hi.

9:56

I'm Aaron Welsh and I'm Aaron Oman Updyke.

9:59

And this is the this podcast will kill you.

10:01

So today we're talking about antibiotic

10:04

resistance.

10:06

Yes, you thought you heard all

10:08

that you wanted to know about antibiotics

10:10

in the last episode. No way, nopeng

10:13

There's so much so fast. There

10:15

is so much more in

10:17

the world of antibiotics to learn

10:20

about, to read about, to hear

10:22

about. And that's what we're doing this

10:24

episode.

10:24

We promise it's not all depressing, like

10:27

it's mostly depressing.

10:29

But yeah, we're going to end it on a hope

10:31

for the future. Nope, absolutely, I think.

10:33

Yeah.

10:35

A couple of things we completely

10:38

forgot Aaron and our excitement to do

10:40

the episode last week to talk

10:43

about why we were so excited beyond

10:45

just the fact that it was antibiotics. It

10:48

was our fiftieth regular

10:50

season episode.

10:51

I totally forgot about that. Oh my gosh,

10:54

I can't believe we've made that many episodes.

10:57

I really can't. I remember, like

10:59

going back to one of the earlier ones,

11:01

and I remember how we used to be

11:03

like, oh my gosh, episode seven, can

11:06

you believe we've made it this far.

11:09

To be fair, I was shocked that we made it to

11:11

seven episodes. So that's fair,

11:13

that's fair. It was a true sentiment at the time.

11:18

The other thing is

11:20

that I completely forgot to mention

11:23

where the first hand account came from in

11:25

the antibiotics episode, and

11:28

that was I mean, it's like we're

11:30

amateurs at this On our fiftieth episode,

11:32

we failed to do the most important things.

11:34

Sometimes the

11:37

days just get to you.

11:39

So that so the first hand

11:41

account from our last episode on antibiotics

11:44

came from a book called The Youngest Science

11:46

by Lewis Thomas. Okay,

11:50

so Aaron to a company

11:52

our quarantine for the antibiotics

11:55

episode, which was penicillin, the

11:57

classic cocktail. What are we

11:59

drinking this week.

12:00

This week we're drinking the plasmid. Oh

12:05

if that's not funny to you, now, it will

12:07

be funny as soon as I explain the biology

12:09

of antibiotic resistance exactly

12:12

exactly.

12:13

And you're like, why are they laughing so hard?

12:15

And what's in the plasmid?

12:17

Great question. It is mezcal,

12:21

like a honey mint, simple syrup

12:24

and lime juice. It's kind of like a

12:26

penicillin, but it's a take on a penicillin.

12:29

It's a plasmid of a penicillin

12:32

exactly.

12:33

It's a plasmid of It's a plasmid

12:35

containing resistance to penicillin. We

12:39

will post the recipe for the alcoholic

12:42

quarantini and the non alcoholic place Berta

12:44

on our website. This podcast will kill you dot com

12:47

as well as all of our social media channels

12:49

any other business I

12:52

don't think, So let's get right to

12:54

it.

12:54

I can't wait. We'll

12:57

take one quick break first, antibiotic

13:21

resistance. Okay,

13:23

it's a big topic, so we're going to break it

13:25

down. Here's how. First

13:28

of all, hopefully everyone's

13:30

listened to the antibiotics episode, so you have

13:32

a framework for how antibiotics work.

13:35

As a very brief overview. Antibiotics

13:38

are designed to either kill or

13:40

halt the growth of bacteria,

13:43

and they do so by targeting various

13:46

elements of bacterial cell walls,

13:48

protein synthesis, DNA replication,

13:51

or metabolism. That's

13:53

our whole episode in ten seconds.

13:56

Well that's a lot shorter than what the episode

13:58

actually turned out to be erin.

14:01

Okay, So the

14:04

question first on a basic level,

14:06

is what are the

14:09

mechanisms of antibiotic

14:11

resistance? Like, how do bacteria actually

14:13

resist these antibiotics?

14:16

Just sheer force of will?

14:18

That's that's the answer episode

14:20

over. Once

14:22

we understand that, then we can ask

14:24

two bigger picture questions, what

14:26

drives antibiotic resistance and

14:29

how does this resistance spread

14:31

through populations? Okay, are

14:34

you excited?

14:35

I'm super excited.

14:36

All right, So what are the

14:38

mechanisms of resistance? First

14:41

of all, you can have intrinsic

14:44

resistance and you can have acquired

14:46

resistance.

14:47

If you are you being bacteria

14:50

right, all right, I'm a bacterial cell.

14:52

You're a bacterial cell. So very

14:54

broadly, intrinsic resistance makes

14:57

a lot of sense in the context

14:59

that a lot lot of our antibiotics come from

15:01

bacterial products. Right,

15:04

So it makes sense that a Streptomyces

15:06

bacteria, for example, will be naturally

15:09

resistant to streptomycin.

15:10

That makes sense.

15:11

Yeah, So that is intrinsic

15:13

resistance, which is neither the

15:16

interesting nor the concerning part

15:18

of antibiotic resistance. So that's all we'll say

15:20

about it. What is both interesting and

15:22

concerning is acquired resistance.

15:25

And there are a few big categories

15:28

of mechanisms by which bacteria

15:31

can evade the effects of antibiotics.

15:33

Let's go through them. Number

15:36

one, bacteria can resist antibiotics

15:39

by changing the target

15:42

enzymes. So what

15:44

does that mean for drugs like quinolones

15:47

that we talked about, fluoroquinolones or

15:50

refampin or the sulfonamides.

15:53

These are drugs that bind directly to certain

15:55

enzymes DNA gyrase or RNA

15:58

polymerase. So if if

16:00

bacteria modify these enzymes

16:02

slightly change their structure

16:04

just a little bit, then these antibiotic compounds

16:07

are no longer able to bind to them.

16:09

Boom, they don't work.

16:11

Makes sense, And that seems

16:13

like a relatively

16:16

easy or like a relatively

16:19

simple mutation would be necessary. Like

16:21

one little.

16:21

Quirk exactly, one little quirk

16:23

for sure. Another

16:26

way. That's actually very similar in

16:30

the case of the classes of antibiotics

16:32

that work by binding too ribosomes

16:35

instead of enzymes. If bacteria

16:37

evolve mutations to their ribosomes

16:40

such that antibiotics can no longer bind,

16:42

then again, boom resistance. That's

16:45

pretty straightforward, right, yeah, Okay,

16:48

So we can alter our enzymes

16:51

that the antibiotics bind to, or we can

16:53

alter the proteins such as ribosomes

16:56

that antibiotics bind to. All

16:58

right, two other ways

17:00

that are also related. Remember

17:04

that gram negative bacteria especially

17:07

have a second membrane that surrounds

17:09

the outside of their cell wall, right,

17:11

and this membrane is less permeable than

17:14

the cell wall is. So we know that

17:16

gram negative bacteria are already

17:18

harder to target with antibiotics because

17:20

of that. So for gram

17:22

negative bacteria, the way that antibiotics

17:25

enter the cells is through

17:27

pores porins little

17:30

channels in the membrane. Well,

17:33

if antibiotics can only enter certain

17:35

porins, and bacteria

17:37

then evolve changes either to

17:39

the type of porins or sometimes

17:41

just to the number of pores on their surface

17:44

that can make them more resistant to certain classes

17:47

of antibiotics.

17:48

Makes sense, makes sense?

17:50

Right? Basically, just changing

17:52

the way that antibiotics are

17:54

able to get into the cell, making it harder

17:56

for antibiotics to get in. Similar

18:00

mechanism is you could kick

18:02

antibiotics out at a faster rate.

18:06

So these are called eflux pumps.

18:09

Mmmm.

18:10

Yeah, bacteria have e flux pumps

18:12

because, especially when they have, especially

18:15

gram negative bacteria that have two

18:18

layers of membrane plus a cell wall, they

18:20

have to be able to get stuff in and out of their

18:22

cells. So eflux pumps are a

18:24

way that they can shuttle molecules

18:27

outside of their cells. And

18:30

it turns out that the genes for these types

18:32

of eflux pumps aren't turned

18:34

on all of the time because

18:37

they can be quite costly. They can lead

18:39

to bacteria exporting too much

18:42

stuff and that can change the

18:44

membrane potential of their cells

18:46

and ultimately lead to cell death.

18:49

Okay, that's interesting, that makes sense too. I

18:51

like that though.

18:52

Yeah, but in the face of antibiotics,

18:54

if you can upregulate those eflex

18:56

pumps, then you can ship the antibiotic

18:59

MOLUCU out of the cell before

19:02

they have time to kill you.

19:03

Right, So it's it's worth it. Even though it's costly,

19:06

it's worth it. In the face of something that is

19:08

actually going to kill you.

19:09

That is like the that's

19:11

like antibiotic resistance in a nutshell,

19:14

it's worth it if the antibiotic is

19:16

going to kill you.

19:17

Yeah, I mean that's that's evolution in a nutshell.

19:20

Yes, Okay,

19:23

So those are the two other ways. You can change

19:25

your eflux pumps, and you can change

19:27

your porins right, make it harder

19:30

for antibiotics to get in or export

19:32

them out even faster. And

19:36

then the last way that

19:38

you can evade

19:40

antibiotics is by changing

19:43

the antibiotics themselves.

19:45

This is my personal favorite mechanism.

19:48

Oohoo.

19:49

Right, So bacteria can

19:51

evolve ways to alter the antibiotic

19:53

compounds themselves and render them

19:55

useless. So for this, I'm going to actually

19:57

go through a couple of examples. There's

20:00

a lot of different ways that bacteria can

20:02

do this, so we'll go through two examples of

20:04

it. The first are

20:07

aminoglycosides, which you might

20:09

remember from our last episode. These are

20:11

streptomycin tobomycin. These

20:13

act on bacterial protein synthesis.

20:16

They bind to ribosomes. Okay, h

20:19

So bacteria can produce

20:21

enzymes naturally, produce

20:23

enzymes that bind to these

20:25

antibiotics and add

20:29

stuff to them, whether it's a phosphate

20:31

or just a little carbon

20:34

group, and that changes

20:36

the structure of the aminoglycoside

20:39

itself so that it no

20:41

longer works. It basically inactivates

20:43

it.

20:45

That seems like much trickier

20:48

to pull off, maybe, but

20:50

they do it really well. It's

20:53

really cool, all right.

20:55

The other most famous example of

20:57

this are, of course, the beta

20:59

lactine maces. Have you

21:01

heard of this?

21:03

Yes, there are enzymes that like actually

21:05

break down the betaalactam ring, right.

21:07

Yes, And the beta lactam ring

21:09

is how betaalactam antibiotics

21:12

like penicillin and cephalosporin actually

21:14

work. So many bacteria,

21:16

especially gram positives, produce

21:19

these enzymes called betaalactamases

21:21

that bind to and inactivate

21:23

that betaalactam ring. It

21:25

is so common, like betaalactamases

21:28

are so common and ubiquitous that

21:30

we actually have a whole nother

21:33

set of drugs that we call

21:35

betaalactamase inhibitors, and

21:37

these drugs inhibit or reduce the

21:40

activity of those enzymes. So it's

21:42

actually really common that when we give

21:44

a beta lactam antibiotic like amoxicillin,

21:47

we give it in combination with a beta

21:49

lactamase inhibitor like clavelanic acid.

21:52

That combination is called augmentin

21:55

mm hmm.

21:56

It's sort of like the lactamase

21:59

inhibitors hold back the little

22:01

guards and they're like no, no, you can invade

22:03

the castle. Okay.

22:04

So there's a

22:07

there's a series of videos that most

22:10

Med students, any Med student listening is gonna

22:12

laugh really hard at that, because we watch these videos

22:15

called Sketchy Micro and they show like

22:17

beta lactams are these rings, and

22:19

then the beta lactamases are these

22:21

little like laser shooters

22:24

that shoot away the beta lactams, and

22:26

then you have like the clabulonic acid that has

22:29

like a armor that comes in anyway.

22:34

I like it. It's really great. It's

22:37

very easy to envision all these as like

22:39

little cartoons for sure.

22:40

Yes. Oh, and they help you learn it a

22:42

lot, a lot easier. Yeah,

22:46

So it's very cool. We already have, like we've

22:49

known that beta lactamases exist

22:51

for so long that we already have drugs

22:54

that specifically target those. But

22:56

what's scary is that now many bacteria

22:58

are what they what we call extended

23:00

spectrum beta lactamese producers,

23:04

so they are making even stronger

23:07

beta lactamases that can break even

23:09

more of our drugs.

23:10

Essentially, Yeah, I mean

23:13

that's sort of the theme, Like this is the

23:15

same story, like over and over

23:17

again, with just tiny variations exactly.

23:19

So then that kind of gets to the

23:21

next question, which is what actually drives

23:24

this resistance? Why is it that we

23:26

have resistance cropping up

23:28

again and again? And we've kind

23:30

of already touched on it, but the basic answer

23:32

is mutation and selection.

23:36

Right, It's a numbers game.

23:37

Yeah, So for resistance

23:39

to happen, first a gene for

23:41

that resistance, any one of those

23:44

types of resistance that I already mentioned, a

23:46

gene for that has to appear in the population.

23:50

And often this happens by random

23:52

mutation, which seems like

23:54

it should be very unlikely,

23:57

right.

23:58

Well, given the generation time and

24:00

how many generations, like even

24:02

within a year or something, a strain

24:05

of E. Cola will have it's not. It

24:07

becomes surprising that there's not resistance

24:09

rather than surprising that there is.

24:11

Would you like to put some hard numbers on

24:13

that, Eric, You know that I would erin so

24:15

mutations like this that can

24:18

provide resistance occur about once

24:20

every ten million cells, and

24:23

because many bacterial species

24:26

divide so frequently, like once

24:28

every half an hour, it would only

24:30

take six hours to get to ten million

24:33

cells.

24:35

And all it takes is one.

24:36

All it takes is one. Okay, okay.

24:39

So that's the first step, right, mutation. You

24:41

have to mutate your DNA in such a way

24:43

that you produce one of those changes.

24:46

And then the second thing that has to happen is

24:49

selection pressure, which essentially

24:51

means you have to wipe out most,

24:53

but not all, of the bacteria

24:56

in a population. So

24:58

let's put some numbers on this again. Let's

25:00

say you have like ten thousand bacteria

25:03

living in a wound on your hand.

25:06

If you killed nine thousand of those

25:08

bacteria by any means, antibiotics

25:11

or otherwise, you have selected

25:14

one thousand survivors. H

25:16

those one thousand survivors will go on to

25:19

reproduce. And

25:22

oftentimes those one thousand survivors

25:24

aren't representative of that whole ten

25:27

thousand group of bacteria, right, They all

25:29

have their own little mutations that are slightly

25:31

different, but those are

25:33

the ones that are going to go on and reproduce.

25:36

So if any of those one thousand had

25:39

the ability to resist an antibiotic.

25:42

Those are going to be the ones that now grow and

25:44

proliferate, right, Okay,

25:47

because remember, like I mentioned, especially

25:49

with eflux pumps, but this is true for many

25:52

of those other mechanisms of resistance.

25:54

A lot of the genes that confer resistance

25:57

to antibiotics are not useful,

26:00

and in some cases they're harmful in

26:02

the absence of antibiotics.

26:05

Right. So you could see over time, if

26:07

you don't put any selection pressure

26:10

on, you know, a bacterial

26:12

strain, as they replicate and replicate and replicate,

26:14

then the resistance genes might drop out

26:16

because it's more costly to maintain exactly

26:19

right.

26:20

Okay, So then how

26:23

does this gene that's present in let's

26:25

say a couple of

26:27

those one thousand bacteria that are left,

26:30

how does it spread through a population

26:33

Because we see antibiotic resistance

26:35

growing at very rapid rates,

26:37

right right. So to understand

26:40

this, we basically just have to know that

26:42

bacteria don't just reproduce

26:45

by fission, right They that's

26:48

how they mainly reproduce, but they

26:51

also can transfer genetic material

26:53

between cells. Okay,

26:57

so this gets

26:59

a get so excited about this.

27:02

I think we talked about this in Ecola right

27:04

with Joshua Letterberg, I think, so who

27:07

discovered this?

27:07

Yeah, So there

27:10

are three ways that bacteria can

27:12

introduce some variety into their

27:14

genes besides just mutation,

27:17

conjugation, transformation,

27:20

and transduction. Conjugation

27:23

is kind of like bacterial sex. So

27:26

basically two bacteria get together,

27:28

they pull out their pillas, and

27:31

then they attach their pillas to their

27:34

partner's pillas, and then

27:36

they can share plasmids. Plasmids

27:38

are circles of DNA, just

27:41

little round nuggets pieces

27:43

of DNA, and they can transfer

27:46

them. So they can like hand a plasmiad to their partner,

27:48

and they can grab a plasmid from their partner,

27:51

and sometimes oftentimes

27:53

those little plasmids have super useful

27:56

things on them, like a

27:58

better eflux pun or a

28:01

new type of betaactamase for

28:03

example. Okay,

28:07

that's conjugation. Transformation

28:09

is when bacteria pick up DNA from the

28:11

environment. So if their neighbor dies

28:14

and explodes and leaves a bunch of DNA

28:16

floating around, another bacterium

28:19

can swim by and pick some of that up. And

28:22

finally, transduction is when viruses

28:25

get involved. So bacteria

28:27

phase which are viruses

28:29

that infect bacteria. Okay,

28:32

these are important.

28:36

These bacteria phasias have to use host

28:38

cell machinery in order to reproduce.

28:40

So what they do is they inject their DNA

28:43

into a bacterium and then some

28:45

of that DNA can get incorporated

28:47

into the bacterial DNA. So

28:51

then every time a virus picks

28:53

up and infects a new bacterium,

28:56

they might transfer a little bit of

28:58

that bacterial DNA to

29:01

a neighboring sell.

29:03

That is super cool. Also,

29:06

we forgot to mention this early on, but

29:09

you will hear a lot more about phages

29:12

and their potential role

29:14

as treatment for antibiotic resistent infections

29:17

later on in the episode from Time

29:19

Stephanie as well, big time, big time.

29:23

So I mean that's pretty much that's

29:25

pretty much how resistance works.

29:28

Okay, So if we go

29:31

back to that population of ten

29:33

thousand bacteria that lives in your

29:35

festering hand wound, Okay, just to kind of

29:38

sum all this up, mm hmm. Actually

29:41

let's call it ten million bacteria.

29:43

Okay, Now my hand wound is really

29:45

really just it's cicy bacteria,

29:48

yep.

29:48

Okay, so you cut yourself, Now you

29:50

have ten million bacteria in the

29:53

cut on your hand, and one of

29:55

them happens to be resistant to penicillin,

29:57

and that's what you went to the doctor, and that's

29:59

what going to use to treat your hand infection. Okay,

30:02

so you take the penicillin and it wipes

30:05

out all but one of

30:07

those bacteria. Right, you

30:09

have just one loan bacterium left.

30:13

That's not a problem for your hand wound necessarily,

30:16

but that single bacterium is

30:18

going to continue to multiply and

30:21

multiply, and now inevitably

30:24

your hand is exposed

30:27

to tons of other bacteria all

30:29

the time. Right, everything you touch is covered

30:31

in bacteria. So eventually

30:34

that one bacterium that was left

30:36

and now reproducing that

30:39

colony that's growing, is going

30:41

to come into contact with some new

30:43

bacteria and he'll probably

30:45

go, hey, just so you guys

30:47

know, if you're planning on making a home here, all

30:50

my friends just got wiped out by penicillin

30:52

recently, and I have this little plasmid.

30:55

It seems really helpful, like I survived.

30:58

So do you want this? Just the

31:00

little betaalactomies? Do you want one?

31:03

And all of the new bacteria're gonna be

31:05

like yeah, heck yeah, I gave me one of those, so

31:08

they'll get together, conjugate

31:10

and share that plasmid with their friends

31:13

in la antibiotic

31:16

resistance.

31:18

I like, I feel like

31:20

we have this this idea

31:22

of an antibiotic resistant bacteria

31:24

to be completely like

31:27

bulletproof basically, but

31:29

your body can still fight off that infection.

31:32

Oh for sure, Yeah, yeah, for sure, for sure. The

31:35

other thing too, though, is that many

31:37

of these antibiotic resistance genes

31:40

come from environmental bacteria, so

31:42

they don't necessarily have to originate

31:45

by mutation in that one bacterium

31:47

that was left behind. They could have been

31:49

introduced from outside populations

31:52

to begin with, and then they can spread

31:54

because of selection pressures.

31:56

Oh yeah, and I'll talk about some of those

31:59

sources resistance.

32:01

I can't wait. So

32:04

yeah, that was a lot, but that was antibiotic

32:06

resistance in a nutshell.

32:08

I loved it. I loved

32:10

it.

32:10

Oh good, I'm so glad. So

32:13

Erin, how the heck did we get here?

32:16

I can't wait to tell you?

32:17

Should we take a quick break first, let's

32:20

do that, so

32:51

Erin.

32:52

You might think that this story the

32:54

story of antibiotic resistance. Maybe

32:57

it starts with the first sulfonamide

32:59

or penicil and resistant strains of bacteria

33:02

that were found in hospitals in the nineteen forties.

33:04

Are you going to tell me it's way further back than that.

33:07

Oh, way, way way

33:09

further back, like millennia, millions

33:12

of years even, Okay,

33:15

okay, so even today,

33:17

like you said, many of the antibiotics that we use

33:20

are compounds produced by microbes, fungi,

33:22

or other bacterial species, And

33:25

in the early years of antibiotics, they were

33:27

all like that, Like synthetic antibiotics

33:29

really only started to become developed in the past

33:31

few decades. And so I think it's

33:34

easy to take it for granted sometimes

33:36

that these antibiotic compounds are

33:39

just produced by these soil microbes

33:41

or fungi and not question

33:43

why exactly they might have evolved

33:46

to produce substances that can kill bacteria,

33:48

because, like you said, when you're producing

33:50

something like that, it can be a costly

33:53

thing, Like it can be a costly thing to kind of

33:55

go above and beyond just simply

33:57

replicating yourself and like getting food.

33:59

I feel like we talk a lot about this in our

34:01

Plant Crossover episodes with Matt, like

34:04

it takes a lot for plants to make these compounds

34:06

that kill us. It takes a lot for bacteria to

34:08

make these compounds that kill other bacteria.

34:11

Yep. It was just like that with the bachulism

34:14

episode, Like why does this toxin exist?

34:16

Yeah?

34:16

So why do these compounds exist in nature?

34:19

They didn't just arise in

34:21

the nineteen forties with penicilin

34:23

like, they've been there for millions of years. Okay,

34:25

so what do these compounds do in nature?

34:28

Yeah?

34:28

So let's just think about a little handful of soil.

34:31

Okay, God side, and you've grabbed some soil.

34:34

In that soil, you have this beautiful,

34:37

complex, rich world of microbes.

34:40

Even though it looks just like a handful of

34:42

soil, it's really like teeming

34:44

with microbial life. And each one

34:46

of these microbes are all pushing and pulling

34:48

and fighting for space and basically

34:51

doing what it takes to continue on to the next

34:53

generation. This is

34:55

a battle that has been going on

34:58

for millions of years, and

35:00

over that time, some microbes have

35:02

evolved strategies to help them stay

35:04

one step ahead of the race to gain

35:07

just a little more ground, and

35:09

antibiotic is one example

35:11

of this type of strategy in nature.

35:14

These antimicrobial compounds actually

35:16

help the bacteria or fungi that produce

35:18

them in any number of ways, like

35:21

to make super durable biofilms,

35:23

or to more easily invade an animal

35:26

cell type three secretion system,

35:29

or to clear the competition in a particular

35:31

area, or to also better

35:33

work alongside another group of bacteria.

35:36

So they actually can help some groups of bacteria.

35:39

And it's also important to remember that in nature,

35:41

the amount of antibiotic compounds produced

35:44

by some of these bacteria or fungi,

35:47

especially those that make something like tetracycling,

35:50

for example, is super

35:52

small, like nowhere near

35:55

what a therapeutic dose would be for humans.

35:58

That is really important to keep in mind.

35:59

Yeah, wow, really important. And

36:02

so when we make

36:04

antibiotics in a lab or in an

36:06

industry setting, you are like farming

36:08

penicillin, like you are like farming

36:11

the fungi in the bacteria. You're making gobs

36:13

and gobs and gobs of it, which wouldn't

36:15

happen in nature. Yeah,

36:17

yeah, or irl

36:24

Okay, So yeah, make a mental note

36:26

of that.

36:26

Okay.

36:28

So even though we may tend to think

36:30

of these antibiotic compounds as these

36:32

brute force drugs that punch holes

36:34

and cell walls or tear apart ribosomes.

36:37

Their role in nature is much more nuanced

36:40

and much more long standing. So

36:44

it makes sense then that if these

36:46

microbes have evolved the ability

36:48

to produce antibiotic compounds over

36:50

thousands or millions of years, the

36:52

bacteria that they are targeting with those

36:54

antibiotics have also evolved

36:56

a trick or two resistance genes.

36:59

Yeah, and this isn't a

37:01

guess, This isn't just like the logical

37:03

flow. Antibiotic resistance

37:05

is ancient, which is actually

37:08

the word for word title

37:10

of a paper that I read, peer

37:12

reviewed paper. And in this paper,

37:15

they analyzed thirty thousand year old

37:17

permafrost sediment to look for genetic

37:19

traces of antibiotic resistance. And guess

37:21

what they found. They found genes.

37:23

They gave resistance to beta lactyms,

37:26

tetracycline, glycopeptides, even

37:29

vancomyocin antibiotics.

37:30

Yeah.

37:31

Wow, so at

37:33

least roughly twenty nine

37:35

thousand and thirty years before penicillin

37:37

was discovered, these resistance

37:40

genes existed.

37:41

Just twenty nine thousand years.

37:43

No big deal.

37:45

Well, I think I think that this at

37:47

least helps to a small degree in

37:49

understanding just how quickly. Some of these

37:51

resistance genes have popped up because,

37:54

like you said, some have arisen just through

37:56

mutation. So some you could take

37:58

you could start in the lab and start with like or

38:00

on a human body and start with,

38:03

you know, a colony of a particular type of

38:05

bacteria, and then you could

38:07

evolve resistance just by applying that

38:09

selection pressure. But I

38:11

think it's also important to remember that some of these

38:14

mutations may be the ones that are a little bit

38:16

more complex. Some of the genes that

38:18

provide resistance to more complex

38:20

antibiotic structures, they

38:23

might have roots already just in

38:25

nature.

38:26

Right, and many many bacteria

38:28

already have these genes. They might just

38:30

not be turned on right

38:32

until they face the selection pressure.

38:34

So that's the other thing, is like they might be there, they're

38:37

just not using them yet.

38:39

Right exactly. You

38:42

know, it's funny erin you say exactly

38:44

right, and I say, right exactly. I've

38:48

noticed this when I'm editing. It's

38:51

very funny to me. Okay, now

38:53

I'm gonna be self conscious about it. Okay, all

38:58

right, So now we have a little bit better idea

39:00

of the ancient roots of some of these

39:03

resistance genes. But how

39:06

do they spread so far and so wide

39:09

so quickly, And you talked about

39:11

the mechanisms of this, so like

39:13

the transfer of genetic material through all

39:15

these different strategies. But

39:17

humans have been a huge

39:19

helping hand, oh in the geographic

39:22

spread of this.

39:23

Bacteria can only move so far,

39:25

Aaron.

39:26

It's true, It's very true. Okay,

39:29

So, Aarin, you asked, how did we get

39:31

here?

39:32

Yeah, And like you always do, I

39:34

always do.

39:35

And I think that's really the perfect

39:37

question to ask about antibiotic resistance,

39:39

because only by understanding what

39:41

has driven the rise of resistance

39:44

are we going to be able to have a chance of

39:47

slowing it or stopping it. And

39:50

you're going to talk a little bit about what here

39:53

actually looks like in terms of how do we get here?

39:55

Right?

39:56

But spoiler alert, it is absolutely

39:59

terrifi.

40:00

Yeah, it's not great. That's

40:03

an understatement.

40:04

It's an understatement. Yeah.

40:08

So, we see widespread multi

40:10

drug resistant bacterial

40:12

species across

40:14

the world, and for

40:16

many microbes, our options

40:19

have completely run out, like

40:21

we are back in the age

40:23

of before antibiotics.

40:26

So far, with maybe one or two exceptions,

40:29

this seems to be a one way street. So

40:31

like resistance seems to be only increasing,

40:34

and we've stopped asking the question will

40:36

antibiotic resistance emerge against

40:39

a particular antibiotic, and now it's just

40:41

a matter of when will it emerge. And

40:44

the state of things has been a long time coming. And

40:46

this massive increase in antibiotic resistant

40:49

bacteria should not

40:51

have come as a surprise to anyone,

40:54

and for many people it didn't. So

40:56

in nineteen forty five, the same year that

40:58

he was awarded the Nobel Prize for his discovery

41:00

of penicillin, Alexander

41:02

Fleming warned about how easy

41:05

it was to make microbes resistant to penicillin.

41:08

And I don't know if I quoted this directly

41:10

in the MRSA episode.

41:12

I think that you did, because we have definitely

41:14

quoted this before. Okay, it's a

41:16

great quote.

41:17

Okay, I don't know if it's the same one, because there were a few

41:20

that I was choosing between. So we'll see

41:22

if I if I was consistent in my choices.

41:25

Okay, So he said specifically

41:27

about improper use. Quote,

41:30

the greatest possibility of evil and self

41:32

medication is the use of two small

41:34

doses, so that instead of clearing up infection,

41:36

the microbes are educated to resist penicillin,

41:39

and a host of penicillin fast organisms

41:42

is bred out, which can be passed to other individuals

41:44

and from them to others until they reached

41:47

someone who gets a septicemia or an ammonia

41:49

which penicillin cannot save. So

41:53

like this was in nineteen forty five, This was a

41:55

couple years after. It was after

41:58

penicillin was introduced to to soldiers,

42:01

and like a year after or the

42:04

year it was released to the public. So you

42:06

know, like we saw it coming, we saw it coming.

42:09

Despite these warnings, penicillin was everywhere.

42:11

It was available over the counter in the US

42:14

until the mid nineteen fifties, and like we

42:16

said, is still available without a prescription

42:18

in many places. It was put

42:20

in cough drops, throat sprays, mouthwashes,

42:23

soaps, you name it.

42:24

Oh my gosh.

42:26

At one point, errand it was even

42:28

available as like a powdered

42:31

daily dose human growth promoter.

42:34

Stop it, yep, Like

42:36

goodbye, powdered peniculian

42:38

to see penicillin.

42:40

Emergency protein powder.

42:42

Just whatever, Just not pop that into

42:45

your antibiotic.

42:46

Laden milk, oh

42:52

dear.

42:52

Yeah, And even though regulation

42:55

slowly increased, it didn't do

42:57

so uniformly, right, and

43:00

even today, antimicrobials or antibiotics

43:02

can still be found in products you never

43:04

would have expected them to, and their

43:07

use is still incredibly widespread

43:10

and not as well monitored,

43:13

especially in some places. Yeah,

43:16

yeah, you know. And as

43:18

we've said a thousand times on this

43:20

podcast, pathogens don't respect

43:22

political boundaries. So

43:25

the rise of an antibiotic resistant strain

43:27

of bacteria somewhere is

43:30

a rise everywhere, right. The

43:32

story of the rise of antibiotic resistance itself

43:35

is pretty simple and pretty

43:37

repetitive. You develop

43:40

a new antibiotic, and then, depending on how

43:42

effective it is and how broad its targets

43:44

are, it becomes the hot ticket item

43:46

and is widely used. And then

43:48

there's a ton of selection pressure, and so

43:50

resistance develops, and then resistance

43:52

spreads quickly as well, and

43:55

then that antibiotic is no longer the miracle

43:57

drug that was promised and gets resigned to the

43:59

backshelf the microbes win.

44:02

Another antibiotic comes along, resistance

44:04

develops, it gets shoved to

44:06

the back shelf, another antibiotic, more

44:08

resistance, rinse, and repeat like This has been

44:10

going on since the

44:13

creation of penicillin, and

44:15

since that time there have been more than one hundred and fifty

44:17

antibiotics that have been developed, and

44:19

resistance has been found for all

44:22

or nearly all of them.

44:25

I watched a documentary called Resistance

44:27

that I really enjoyed, and I'm going to borrow

44:29

one of the graphics that they presented and put

44:32

it in audio form as a way of illustrating

44:34

the rise of resistance, because it's kind

44:36

of amazing to see just

44:38

how quickly it became

44:40

like widespread, Yeah, so

44:43

okay. Sulfonamides

44:45

introduced nineteen thirty five, resistance detected

44:47

nineteen forty. Penicillin nineteen

44:50

forty two, introduced resistance

44:52

nineteen forty five, Streptomycin introduced

44:54

nineteen forty four, resistance nineteen

44:57

fifty eight. Tetracycline introduced

44:59

nineteen forty eight, resistance nineteen fifty

45:01

four, chlorum phenacol introduced

45:03

nineteen forty nine, resistance detected nineteen fifty

45:05

six, and so on and so on, like this

45:07

goes. I could list this with like ten

45:10

more antibiotics that

45:12

you would recognize by name. It's

45:15

it's incredible, and

45:18

so it became increasingly apparent,

45:20

obviously, as we are aware

45:22

today that resistance is inevitable.

45:25

It's just like thanos just

45:28

another reference, another

45:30

marvel mar reference. But

45:33

resistance is what we expect,

45:36

and the discovery of plasmids and the

45:38

ability of bacteria to transfer genes

45:40

not just within species but across

45:42

them in the nineteen fifties is when

45:44

those things were kind of discovered or developed.

45:47

That helped us a lot in terms of

45:49

understanding the mechanism

45:52

and how these bacteria were able to gain

45:54

resistance so quickly and how it could spread

45:56

so rapidly. But still

46:00

enthusiasm for these miracle drugs,

46:03

and maybe like our own hubris that we

46:05

could, oh, we'll we'll just keep going digging

46:07

in the soil, or we'll go here and there and we'll

46:09

just keep finding new soil

46:11

bacteria to make new antibiotics.

46:15

Like that maybe also

46:17

blinded us to the horrific

46:20

implications that these

46:22

discoveries carried.

46:23

Right.

46:24

The development of antibiotics in the twentieth century

46:27

was arguably the most impactful, or

46:29

at least one of the most impactful medical

46:32

advancements that we have ever seen. Like

46:34

it must have been incredible, yeah,

46:36

but within a matter of decades we

46:38

seem to be witnessing the rise and

46:41

fall of these wonder drugs So

46:43

the big question is where did we go wrong?

46:46

The short answer is through overuse

46:48

or improper use in both

46:50

medical and agricultural settings.

46:53

So let's dive a little bit deeper into.

46:55

Each as we are wont to do.

46:59

Let's start with medical side of things. As

47:02

I've mentioned before, once they came onto

47:04

the scene, antibiotics were indiscriminately

47:06

used for anything that might

47:08

be could be possibly

47:10

was a bacterial infection. And

47:13

they were even used preventatively, right, And

47:15

they still are used preventatively.

47:17

That's true. Actually, we still in surgery

47:19

and stuff. Yeah, yeah, it's like in

47:21

surgery though, it like really reduces mortality.

47:24

Right right, right, and so yeah, and so I think

47:27

one thing that I want to get across is that antibiotics

47:30

still should be used. Like they're not bad

47:32

things. They're still hugely important, but

47:35

we need to really consider how we

47:37

use them so that we save them

47:39

for when we really need them

47:41

need right. So it's sort of proper

47:44

use, right, and not saying it's it's reducing

47:46

their overuse and turning

47:48

improper use into proper.

47:49

Use, right yeah, yeah, yeah, totally.

47:52

Because resistance will continue to happen, but at

47:54

least we can slow it down a bit. Okay,

47:57

So on the medical side

47:59

of things, I see is falling into three different

48:01

issues. So the first lies

48:03

with improper prescription, and

48:06

so, particularly in the earlier days of antibiotics,

48:08

this was a huge issue, but it also has

48:10

continued to be a huge issue because

48:13

there sometimes might be a thought that like, okay,

48:15

if there's a ninety five percent chance that an infection

48:18

is viral and a five percent chance that

48:20

it's bacterial, you might just want

48:22

to prescribe an antibiotic anyway, because

48:24

if it's bacterial, then you could wipe out

48:26

that infection and reduce the suffering of your patient.

48:29

And if it's not, well, what's the harm to that patient.

48:32

It's thought on an individual patient

48:35

level scale, right, and that makes

48:37

sense, And

48:39

jumping ahead a bit, a study

48:41

showed that in twenty ten, eighty

48:44

percent of primary care doctors and seventy

48:46

percent of emergency room doctors were

48:48

prescribing antibiotics for acute bronchitis,

48:52

which is viral almost always, viral

48:55

almost always, and so then that's how we get into the

48:57

almost always issue. So it's sort of a

48:59

matter of treating the individual versus considering

49:01

the group as a whole. It's a very tricky decision.

49:05

It's a very tricky situation.

49:06

A thing I think a lot about because

49:09

my whole background is in public health

49:11

and like thinking about these

49:14

things on a population level, and

49:16

now I'm going into medicine where you're like concerned

49:19

about the patient in front of you, and there's often

49:21

a conflict between what's best for the individual

49:23

patient and what is best for the public.

49:26

And it is a tricky landmine.

49:29

Mmmmmmm hmm.

49:30

Yeah.

49:32

Yeah, And I'm not going to talk about what

49:34

we should do and the ways we

49:36

should change it, but I think the consensus

49:39

is is that we do need

49:41

to change sort of the directives

49:44

of this. Yeah, we change how we use

49:46

them.

49:46

Like, antibiotics

49:49

are also not benign, right,

49:52

Like we talked about this in the last episode.

49:54

They have side effects, right, They're wiping out your microbiome.

49:56

They're going to cause side effects, So they're also not

49:59

benign to give a patient, to

50:01

give a person antibiotics if they

50:03

don't really need them.

50:05

Right, And this is something that we're becoming more

50:07

and more aware of as

50:09

we talk about the microbiome. And some ambiotics,

50:12

like you said, are also toxic

50:14

in themselves, like they damage

50:16

certain organs so it's yeah,

50:19

and then there's also just sanitation

50:21

issues within hospitals. So I mean, when

50:24

you're in a hospital, the rate of

50:26

people that have infections, it's

50:28

high. Infections are very high, They're very

50:30

prevalent. And this is talking about drug

50:32

resistant and drugs and

50:34

antibiotics susceptible infections, right,

50:38

and this makes transfer between patients

50:41

really easy. And this just speaks

50:43

to the nature also of how equipped these bacteria

50:46

are to keeping their foothold

50:48

in a place and surviving, Like some of

50:50

these are really really difficult to get

50:52

rid of. Yeah, and

50:54

so a hospital just provides tons

50:56

of opportunities for bacteria

50:58

to exchange info and to settle onto

51:01

the skin or into the surgical incision site,

51:03

or into the intestine of someone who happens

51:05

to be in the hospital. Finally,

51:08

there's the third issue, which is that people

51:10

who are prescribed antibiotics might not

51:13

take them properly, so they

51:15

might not finish their course. By that, I

51:17

mean, if you're prescribed ten days of in an antibiotic and

51:19

you only take five because you start feeling better,

51:22

all you've done is kind of train the bacteria

51:24

in your body to become resistant. And

51:27

so if that happens and you get severely

51:29

sick, and then you have to go to the hospital, and

51:31

then you're bringing your drug resistant bacteria

51:34

into the hospital. Yeah, she's like, come

51:36

on, which is not

51:39

good. And then that same

51:41

twenty ten study that I mentioned just a little

51:43

bit ago, they also showed that up

51:45

to forty percent of people fail to complete

51:47

their full course of antibiotics.

51:49

Oh yeah.

51:50

And so these three healthcare issues have

51:52

been a part of what is driving intibiotic resistance

51:55

in hospital and community settings. And

51:57

for the most part, I have to say that a dozen

52:00

like, we have made some forward progress

52:02

in terms of regulating them, but it's

52:05

we still have a long way to go. Okay,

52:08

but that's just the medical side of things. We're only

52:10

getting started. No,

52:13

this is horrifying because even if

52:15

tomorrow we enacted all of those

52:17

changes, it might slow down the spread

52:19

of resistance in healthcare settings, but it

52:21

wouldn't stop the problem entirely. And

52:24

a small part of that is due simply

52:26

to the nature of resistance. It's due

52:28

to this arms race of bacteria and antibiotic

52:30

compounds. Resistance will always

52:32

evolve. But another huge

52:35

part is improper antibiotic

52:37

use in agriculture. And

52:40

we talked a bit about this in the last episode,

52:43

but I want to go more into the history of this since

52:46

it's such an integral part of the story

52:48

of resistance. So this history

52:51

starts with yet another chance discovery

52:54

when a researcher was looking for a

52:56

natural source of B twelve to supplement

52:58

the food of chickens to help them better. So

53:01

he learned that streped to mices areo

53:03

facins, produces vitamin

53:06

B twelve during the fermentation process

53:08

from making stripped micin. So

53:10

he was like, Hey, can I have some of

53:12

that waste from fermentation, just

53:14

like the leftover gunk or whatever. I'm

53:17

gonna mix it into the chickens food and

53:19

just see what happens, okay, And the

53:21

results were remarkable,

53:24

like the chickens grew tremendously much

53:27

faster than he expected due to just

53:29

B twelve, and so did the piglets

53:31

that he also tried it out on. He

53:34

was like, Okay, is it actually

53:37

the B twelve that's in the fermentation

53:39

waste or is it trace amounts of the

53:41

antibiotic that's causing this

53:43

growth? And maybe he

53:46

was like, well, maybe it's suppressing gut like harmful

53:48

gut bacteria or something else,

53:51

like, regardless of the reason, he couldn't

53:53

deny that they were actually having an effect. So,

53:56

on average, livestock that were fed

53:58

these growth promoters grew three

54:00

to eleven percent faster than their non antibiotic

54:02

ridden counterparts. But I've seen actually much

54:05

higher rates quoted, particularly

54:07

early early on in these experiments.

54:10

Oh and this led

54:12

to because you could make more

54:14

meat faster, you could sell

54:16

more meat, and so consumption overall

54:20

really grew. And then it kind of in

54:22

that way firmly established these

54:25

growth promoters, so called growth promoters,

54:27

as a necessary part of agriculture. And

54:30

so I'm going to use the term growth promoters

54:32

a lot, and that basically means these trace

54:34

amounts, so like non therapeutic doses

54:37

of antibiotics that are included in food

54:39

for animals like

54:41

agricultural animals, livestock. Ok okay,

54:46

so these antibiotic laced foods

54:48

plus preemptive treatment, so

54:50

like not just as growth promoters,

54:52

but actually like, oh, we're going to dose you so

54:55

that you don't get this or that ulcer

54:57

or whatever. That led to

55:00

some farmers just packing them

55:02

all in all these animals in as tightly

55:05

as possible because they were secure

55:07

in the knowledge that the crowd diseases

55:09

that they had previously been worried about wouldn't

55:12

be much of a concern with these antibiotics. And so

55:14

it really led to the rise of like the

55:16

industry some of the more the

55:19

nastier sides of the industry that we see.

55:21

Wow, yeah, yeah,

55:23

I did not know that part of it, but

55:26

that makes so much sense. M M.

55:30

And the drug companies that were producing these antibiotics

55:33

ate it up, or rather they were enthusiastic

55:35

about the livestock eating up their

55:38

antibiotic fermentation waste products because

55:40

this was all stuff that was like they were just throwing

55:42

it away anyway, so it's

55:44

great for them. So sub therapeutic

55:47

doses of antibiotics were sold as growth promoters

55:49

starting the nineteen fifties, and the

55:51

huge threat of antibiotic resistance

55:54

had been known and discussed

55:56

for at least a decade before that, and

56:00

this basically provided the perfect

56:02

breeding ground for antibiotic resistance

56:05

because if you think about like think about

56:07

a industrial farm full

56:09

of pigs packed in, you know, all close

56:12

to one another, and then they're all

56:14

just just with antibiotics, like

56:16

the bacteria that they can

56:18

move so easily that way. Resistance

56:21

can move so easily that way, like it's and

56:23

manure is one of the best sources

56:25

for anbiotic resistance bacteria apparently,

56:29

and then there's runoff. Okay

56:31

anyway, and it wasn't

56:33

just restricted to growth promoters

56:35

and food farmers began toying

56:38

with different ways to deliver the antibiotics

56:40

to the animals, so they were like in

56:42

the water before they were slaughtered. Like,

56:44

here's some water injected

56:47

injected into the

56:49

areas for prime cuts. What

56:53

painting painting raw

56:55

steak with antibiotics

56:58

or mixing them in with round beef.

57:02

I'm sorry, why would you mix

57:04

it in with the meat that you're selling

57:06

to humans? What is the purpose

57:08

of that?

57:09

Well, because then you could it has a longer shelf

57:11

life.

57:13

Are you kidding me?

57:14

I'm not kidding you. Oh

57:17

dude. Spinach was even

57:20

washed in streptomycin. I'm

57:23

so serious.

57:28

Don't chicken eat We're sold in.

57:32

Chickens were literally sold

57:34

soaking in antibiotics

57:37

because that would lengthen their shelf life. My

57:40

face, so like you could squeeze

57:42

out like the chicken juices from a raw chicken

57:44

at the grocery store back then, and

57:46

you could get like antibiotics

57:50

in those juices. The

57:53

world got its first taste of how the

57:55

use of antibiotics on farms bled

57:57

into human life in the nineteen fifties. So around

57:59

the same time when it was first

58:01

started to ramp up.

58:02

Oh my god.

58:05

Around this time, penicillin had

58:07

been made prescription only in the US

58:09

and in Britain, partly because

58:11

the rates of penicillin allergy were just

58:13

like skyrocketing. And so with

58:16

these increased regulations, physicians

58:18

and epidemiologists expected to see fewer

58:20

penicillin allergies crop up. Makes sense,

58:23

right, No,

58:25

that's not what they saw. Instead,

58:28

they saw an increase, they saw surge.

58:30

And it turns out that the source of the penicillin.

58:33

This is done through like a lot of detective work.

58:35

The source of the penicillin was

58:38

in the milk that people were drinking.

58:41

Some milk contained so much penicillin

58:44

that it could have been sold as a drug, those

58:47

therapeutic doses, yes, Groad.

58:51

So this finding led the FDA

58:53

at least to rule that you could no longer treat

58:56

meat with antibiotics prior to it being

58:58

sold.

58:58

Okay, so, like my stakes

59:01

are not washed in antibiotics anymore.

59:03

No, No, that's all.

59:05

Done, small blessings.

59:10

Yeah, but yeah,

59:13

this did nothing to stop the addition

59:16

of antibiotics in feed for animals

59:18

as a growth promoter. And

59:21

then there was a series of studies in the nineteen

59:23

sixties that clearly demonstrated that growth

59:25

promoters led to the rapid development

59:28

of resistance in microbes, colonizing

59:30

both the animals as well as

59:32

the people working with the animals.

59:34

So like this was a kind of a cut and dried, very

59:37

eye opening experiment. Fortunately,

59:41

this was taken somewhat seriously

59:43

by governments. So the UK took

59:46

action early on in limiting antibiotic

59:48

use and agriculture. Starting

59:50

in nineteen seventy one, they banned antibiotics

59:52

as growth promoters if those antibiotics

59:55

were used to treat disease in

59:57

animals and humans.

59:58

Okay, so you can I no longer use tetracyclines

1:00:01

because we use those to treat disease

1:00:04

for example.

1:00:05

Yeah, got it. And you had to have a prescription

1:00:07

for them if you wanted to use them therapeutically.

1:00:10

Okay.

1:00:10

And the US was like this close

1:00:13

to following suit, but

1:00:16

you know, we didn't

1:00:19

a little bit after this decision in the UK,

1:00:21

the FDA was like, I'm

1:00:23

going to lay down the law and we're going to limit the use

1:00:26

of antibiotics purely to therapeutic

1:00:28

purposes. But then the mighty

1:00:30

dollar of the agricultural industry

1:00:32

overruled. Representative

1:00:35

Jamie Whitten, who was like part

1:00:37

of the spokesperson for this industry,

1:00:40

basically said that

1:00:42

he would hold hostage the budget of the

1:00:44

FDA if the regulations passed, and

1:00:47

so because he had somehow he had

1:00:49

that power aeron I don't know, So

1:00:52

the White House gave in since the

1:00:54

budget hold up would have also hurt many

1:00:56

other important projects, and

1:00:59

so Witten, the representative, insisted

1:01:01

that the data in support of banning the use

1:01:03

of non therapeutic antibiotics in agriculture

1:01:06

was incomplete and biased against farmers.

1:01:09

And so then they were like, okay, well, we want

1:01:11

the farmers. We want the

1:01:13

agricultural industry to design their own

1:01:16

projects and do their own research to

1:01:18

figure out what the truth is.

1:01:20

Oh, there's no bias there at all, right.

1:01:23

I mean, the burden of proof has been

1:01:25

on epidemiologists and

1:01:27

researchers to find that

1:01:29

antibiotic use in agricultural

1:01:32

settings leads to antibiotic resistance

1:01:35

that is clinically

1:01:37

important in humans. Yeah right,

1:01:40

But this insistence that those studies were

1:01:42

inaccurate or that the research was incomplete

1:01:44

was just a flat out lie because

1:01:47

in the nineteen seventies a researcher

1:01:49

named doctor Stuart Levy wanted to see

1:01:51

how rapidly resistance could develop

1:01:54

or spread in livestock given these growth promoters,

1:01:57

So he tested out some young

1:01:59

chickens who are given tetracycline. Within

1:02:02

thirty six hours of first being

1:02:04

given the feed laced with tetracycline, their

1:02:06

gut E. Coli was resistant

1:02:09

thirty six hours. So that's scary

1:02:12

enough. And tetracycline is like was a

1:02:14

broad spectrum, just like awesome

1:02:18

used drug was

1:02:21

was. And so that's

1:02:23

scary enough on its own. But what made

1:02:25

it even scarier is that over the next three

1:02:27

months, the E. Coli also added

1:02:29

to its arsenal genes that made

1:02:31

it resistant to ampicillin, stripped

1:02:34

to miceine, and sulfonamides, and

1:02:36

the chickens had never even received

1:02:38

any of those drugs. Whoa

1:02:41

the tetracycline had acted like a call

1:02:43

to arms for these bacteria, like

1:02:46

we've faced and defeated one antibiotic, so

1:02:48

we need to be prepared for any others that might come

1:02:50

our way, Man oh Man,

1:02:53

And I bet you didn't think that the study could show

1:02:55

even more concerning results, but it did,

1:02:58

and you're not going to be surprised by them. But Levy

1:03:01

found the same antibiotic resistance

1:03:04

in the gutty coli of the farmers

1:03:06

and the families of those farmers

1:03:08

that had kept the chickens, none

1:03:11

of them had received tetracycline.

1:03:14

There have been literally dozens,

1:03:18

dozens and dozens of peer reviewed articles

1:03:21

demonstrating clearly that antibiotic

1:03:23

use in animals impacts humans. To

1:03:26

epidemiologists and physicians and

1:03:28

microbiologists and biochemists, whether

1:03:31

or not rampant use of sub therapeutic

1:03:33

levels of antibiotics was leading

1:03:36

to a huge increase in resistance

1:03:38

and resistant organisms, that

1:03:41

wasn't a scientific question, It

1:03:44

was firmly established that it was.

1:03:46

Instead, it was a political one. Does

1:03:49

it sound familiar?

1:03:50

Sounds too familiar, Aaron?

1:03:53

Yeah. And despite

1:03:56

this strong evidence that growth promoters

1:03:58

also promoted antibiotic resistance and

1:04:01

all of the terrifying implications that came along

1:04:03

with it, the US declined to ban tetracycling

1:04:06

as a growth promoter, It, along

1:04:09

with many other antibiotics, continued to be used

1:04:11

freely for decades. In livestock, you.

1:04:14

Said, for decades.

1:04:17

Are you gonna tell me some happy news at the end of

1:04:19

this, like no longer or what?

1:04:22

There are some some bright moments

1:04:25

and some really cool

1:04:27

little case studies that I won't go into, but

1:04:29

I'll mention, and I'll mention places to read

1:04:32

further about them. Because Denmark

1:04:34

and Netherlands, whoo whoo okay,

1:04:39

And just because a country had stricter regulations

1:04:43

doesn't mean that they weren't also

1:04:45

contributing to the resistance problem. A

1:04:48

lot of the time, there wasn't much regulatory

1:04:50

oversight into just how much

1:04:52

antibiotics were being sold to agriculture,

1:04:56

and when there was sort

1:04:58

of a retrospective look

1:05:00

at the amount over time, like number

1:05:02

of tons or millions of pounds sold

1:05:04

over time, there actually wasn't

1:05:07

really a decrease after some

1:05:09

of these bands were put into place, because

1:05:11

the labeling just changed for a lot

1:05:13

of these things. Another

1:05:15

issue was that these bands, like I mentioned,

1:05:18

often limited use of antibiotics

1:05:21

to those that weren't also used to

1:05:23

treat animal or human infections. But

1:05:26

this is also a problem, and

1:05:28

that's because as resistance to the most

1:05:30

common antibiotics grew, doctors

1:05:33

had to reach increasingly to

1:05:35

the back of that cabinet for the third and

1:05:37

fourth string, antibiotics that had been deemed

1:05:39

too toxic, or too specific, or too

1:05:41

expensive to be used. Fankomycin

1:05:44

was one of these antibiotics. It

1:05:47

kind of came. It was one of

1:05:49

the earlier ones that had been discovered

1:05:52

and developed, but it

1:05:54

was deemed to be too expensive

1:05:57

and had some nasty side effects, so

1:05:59

people were like, nana, we'll just use methicillin instead,

1:06:04

and so in the

1:06:06

nineteen eighties it was dusted off

1:06:08

and increasingly used to treat stubborn

1:06:10

resistant infections, and it

1:06:12

seemed to be remarkably effective in

1:06:14

that microbes weren't showing resistance towards

1:06:17

it, so that was promising, and

1:06:19

some researchers were like, Okay, well,

1:06:21

how exactly does it work? And

1:06:24

they were like, it's so complex that

1:06:26

it would be nearly impossible for a

1:06:28

bacterium to develop all of the genetic

1:06:30

changes needed to overcome this mechanism.

1:06:34

It's like an unsinkable ship. Like why

1:06:36

do we say these things. It's

1:06:38

just tempting fate. In nineteen

1:06:41

eighty nine, the first strains of

1:06:43

vancomized and resistant entercocci

1:06:45

VRE started popping up in hospitals

1:06:47

in the US, and by nineteen ninety three it

1:06:50

was close to being endemic in many hospitals.

1:06:53

VR baby, VR baby,

1:06:57

It's really bad. Within five

1:07:00

years for showing up, VRE was

1:07:02

widespread in the US, something

1:07:04

that it took MRSA about methicillin

1:07:07

resistant staff oreas about

1:07:09

fifteen years to do. So

1:07:12

they were like, what the heck? This is super

1:07:15

complex, So how could

1:07:17

there have been enough time that has passed for

1:07:19

these mutations to actually emerge? Like,

1:07:22

what is going on here? What happened? Turns

1:07:25

out the answer is an agriculture.

1:07:28

A vancom ioson like antibiotic

1:07:30

had been used as a growth promoter in

1:07:32

livestock for decades. Oh gosh,

1:07:35

And so when physicians started to reach into

1:07:37

the back of that cabinet for vancom ioson,

1:07:40

the resistance genes were already long

1:07:43

present and quite prevalent, and

1:07:45

then with that added selection pressure of

1:07:47

being used in a clinical setting, it just spread

1:07:50

like wildfire, and

1:07:52

bad turned to worse when

1:07:55

in nineteen ninety six, the first vancom

1:07:57

iceon resistant staff OUREUSSA

1:08:01

infections. VERSA infections

1:08:03

emerged in Japan. At

1:08:06

this point in time, about fifty

1:08:08

percent of all hospital staff OREUS

1:08:10

infections were methicone resistant, so

1:08:13

treatable only by vancom iyosin. Within

1:08:16

the next few years, versa was

1:08:18

basically everywhere, And

1:08:21

again there was still

1:08:23

lobbying for the continued use of

1:08:25

vancom iosin and other antibiotics as

1:08:27

growth promoters in the US, and

1:08:30

those lobbyists still refuse to acknowledge

1:08:32

how those practices could lead to resistance.

1:08:35

So Robert Carnival, who is one of

1:08:37

these lobbyists, is quoted as saying,

1:08:40

I'm sure vre can transfer from animals

1:08:43

to people and it might be resistant, but

1:08:45

is it of clinical importance?

1:08:49

Yes, yes, yes it is, yes,

1:08:52

oh gosh.

1:08:53

And it wasn't just vanca icein resistance

1:08:55

that agriculture was promoting. Calliston

1:08:58

was another one of those antibiotics that had put

1:09:00

aside in favor of more sensitive drugs

1:09:02

in the past, and it had

1:09:04

also been used in agriculture, and so

1:09:06

resistance was already super high there.

1:09:10

And it wasn't just resistance genes

1:09:12

that spread from agricultural settings to hospitals

1:09:15

or communities. People realized

1:09:17

it was also the bugs themselves, epidemics

1:09:20

of xpec which I can't

1:09:22

remember what that one is, but it's some sort of

1:09:24

ecoli, toxic ecoli. Yeah,

1:09:28

these UTIs caused

1:09:30

by xpecs. They seemed

1:09:32

to be coming from food, specifically chicken.

1:09:35

Oh gosh, quinnolone resistant Salmonella

1:09:37

typhomerium strain DT one

1:09:39

O four that's a bad

1:09:42

one that spread through fresh dairy and

1:09:45

can kill you, and that

1:09:47

came directly from animals, and quinnolone

1:09:49

resistant Campilo bacter those

1:09:52

that was found in grocery store chicken.

1:09:54

Oh gosh.

1:09:55

So quinnilone had been used in agriculture

1:09:57

for years, but the sharp, alarming rye

1:10:00

of resistance to it prompted the

1:10:02

FDA finally to propose

1:10:05

a ban, propose a ban for

1:10:07

their use in animals, but a

1:10:10

proposal was just a proposal. Some

1:10:12

drug companies, including Bayer, declared

1:10:15

that it would not comply voluntarily, so

1:10:17

it would fight the proposal and ask for a hearing

1:10:20

where it could show that quinn alone use in animals

1:10:22

was of no harm to humans.

1:10:24

I'm just getting too depressed, Darren.

1:10:26

I know, okay, but

1:10:29

In the late nineteen nineties, it is a little shining

1:10:31

sun. The European Union moved

1:10:33

to ban antibiotics as growth promoters

1:10:36

like all of them, but preventive

1:10:38

use was still allowed, which still promoted

1:10:40

resistance. Again, there didn't

1:10:43

seem to be any decline

1:10:45

in the amount of antibiotics sold for farm

1:10:48

use, so from nineteen ninety nine

1:10:50

to two thousand and six and beyond it

1:10:52

stayed at six hundred and six tons per

1:10:54

year. This is after the ban, right

1:10:57

However, However, some

1:11:00

countries did actually do it on their own, and

1:11:02

some countries, like in Denmark,

1:11:05

the industry did it on their own themselves.

1:11:07

They were like, we're not gonna We're

1:11:09

not gonna listen, like they were just decided amongst

1:11:12

the community and the

1:11:14

farmers that they were going to do this because they

1:11:16

were like what's.

1:11:16

Right for you know, everyone

1:11:20

kind of thing.

1:11:21

Yeah, So the Netherlands, for example,

1:11:23

they really doubled down and started policing

1:11:25

the use of antibiotics much more, and

1:11:28

the result was that antibiotic use on farms

1:11:30

actually declined dramatically starting

1:11:32

in twenty thirteen and really

1:11:35

cool. The occurrence of antibiotic resistant

1:11:37

bacteria found in meat also declined,

1:11:41

and similar things happened in Denmark as well,

1:11:44

And all of the horrible repercussions

1:11:46

that had been promised, like a drop off

1:11:48

and the weight of livestock sky high

1:11:50

meat prices, more disease among

1:11:52

livestock, none of these

1:11:54

things happened. H

1:11:58

The weight dropped a bit, a

1:12:00

little bit, but it had

1:12:02

been recognized for quite a while that growth

1:12:04

promoters were no longer achieving the

1:12:07

same dramatic gains that had been seen

1:12:09

when they were first used. Oh

1:12:11

no, So somewhere inesting that

1:12:14

is very interesting. So

1:12:16

somewhere in the five or six decades

1:12:19

since antibiotics were first used in agriculture,

1:12:22

they had lost their magical

1:12:24

ability to promote growth.

1:12:27

So a couple of different things. It's

1:12:30

probably likely that when they were first used,

1:12:32

the antibiotics were compensating for some of the

1:12:34

negative ways that the farms were run, so

1:12:37

like as hygiene and monitoring and

1:12:39

nutrition and breeding had changed, it

1:12:41

had eliminated that gap that growth

1:12:43

promoting antibiotics had made up. And

1:12:46

it's also possible that if it was

1:12:48

affecting the negative, the harmful

1:12:51

gut bacteria or whatever gut bacteria,

1:12:53

that resistance had emerged and so

1:12:56

antibiotics were literally just doing nothing.

1:12:58

Doing less.

1:12:59

Yeah yeah. And by removing

1:13:02

antibiotics from agriculture, places

1:13:04

like Denmark and the Netherlands incorporated

1:13:06

animal welfare into the business model,

1:13:09

and with that they improved quality, quality

1:13:11

of life for the animals, quality of meat for

1:13:13

consumption, quality of their investment,

1:13:16

et cetera. But once again, the

1:13:18

US failed to make similar regulatory

1:13:21

progress as Europe.

1:13:23

In twenty fifteen, thirty four

1:13:25

point three million pounds of antibiotics

1:13:27

were sold for use in animals, compared

1:13:29

to approximately seven point seven million pounds

1:13:32

for humans. But even

1:13:34

though the US government agencies

1:13:36

were slow to stop the over use and misuse

1:13:38

of antibiotics, some companies actually

1:13:41

voluntarily stopped using growth

1:13:43

promoters because they realized

1:13:45

that antibiotics for growth promotion may

1:13:48

not be worth the cost for human

1:13:50

health or the cost of the constant

1:13:52

legal battles. This

1:13:54

industry shift paralleled many others

1:13:56

that were going on in food supply arenas,

1:13:59

so it was one after another, both

1:14:02

from the meat

1:14:04

providing side of things, so these big

1:14:07

name chicken farms

1:14:10

to the food supply aspect,

1:14:12

so like fast food restaurants, stuff like that, they

1:14:15

were all starting to offer antibiotic

1:14:17

free meat options, and so the

1:14:19

market seemed to be responding positively

1:14:21

to these changes, but

1:14:24

that's all on the industry side.

1:14:27

So even though starting in twenty twelve, the US

1:14:29

has put in some regulations for monitoring

1:14:31

the use of antibiotics and agriculture, for

1:14:34

many years, the amount of antibiotics

1:14:36

has actually increased rather

1:14:39

than decreased. Twenty

1:14:41

seventeen did see a decrease, but

1:14:43

it doesn't seem one hundred percent clear

1:14:46

why that decrease happened. Maybe it's

1:14:48

because of these bands, and that would be great, But

1:14:51

antibiotic resistance and its association

1:14:53

with agriculture is a perfect example

1:14:55

again of why a one health approach

1:14:58

is essential. And

1:15:00

animals share one bacterial and viral

1:15:02

world, and fungal world and protozol

1:15:05

and parasitic whatever. So the

1:15:07

rise of antibiotic resist in't bacteria

1:15:09

on farms means a rise of antibiotic

1:15:12

resistant bacteria everywhere. Just

1:15:16

like with the medical side of things, there

1:15:18

is such thing as proper use of antibiotics

1:15:21

in agriculture, but there

1:15:24

has been overuse

1:15:26

in terms of growth promoters and in terms

1:15:28

of preemptive treatment, and

1:15:30

it has remained a debate and

1:15:33

a challenge to kind of see what

1:15:36

the cost and benefits are. And

1:15:38

I think we're only

1:15:40

becoming more and more aware of

1:15:42

the cost to humans. And it's also

1:15:45

not going to just be antibiotic resistant

1:15:47

infections in humans. It's also going to

1:15:49

be livestock as

1:15:51

well. So it's an interesting

1:15:53

thing to think about anyway. But it's

1:15:56

not just the US where overuse

1:15:58

is an issue. Twenty fifteen,

1:16:00

a group of researchers tried to predict how

1:16:03

much antibiotics Brazil, Russia,

1:16:05

India, and China could be predicted to use

1:16:07

in the next fifteen years as

1:16:10

demand for meat continues to increase.

1:16:12

If nothing changed, that estimate was one

1:16:15

hundred and five thousand, five

1:16:17

hundred and ninety six tons

1:16:20

globally. Oh dear,

1:16:23

that's hard to wrap

1:16:25

your brain around. The

1:16:27

annual numbers of antibiotic resistant infections

1:16:30

and deaths due to those infections are

1:16:32

absolutely staggering. The

1:16:35

history of resistance is like actively

1:16:38

still being written, and it's

1:16:40

not looking good. I

1:16:44

want to I mean, there are some promising

1:16:46

avenues of research ahead of us, but

1:16:49

I want to end with a quote from the

1:16:51

amazing book Big Chicken by Maren

1:16:53

McKenna. Antibiotic

1:16:56

resistance is like climate change. It

1:16:58

is an overwhelming threat created

1:17:00

over decades by millions of individual

1:17:03

decisions and reinforced by the actions

1:17:05

of industries. It

1:17:07

is also like climate change in that the

1:17:09

industrialized West and the emerging economies

1:17:12

of the global South are at odds well

1:17:15

with that. Erin, tell

1:17:17

me where we stand with antibiotic

1:17:20

resistance today. Are we basically

1:17:22

on the brink of returning to a pre antibiotic

1:17:24

era? Is there any hope?

1:17:27

I mean, let's find

1:17:29

out I need a short

1:17:31

break. Yeah. Same, Well,

1:18:06

let's start with the depressing things and

1:18:08

then we'll end on a

1:18:10

at least hopeful

1:18:13

note. How about that? Great? Okay?

1:18:17

Ah, all right? So medically

1:18:21

in the US, at least, the

1:18:23

CDC estimates that at least forty

1:18:26

seven million antibiotic

1:18:28

prescriptions in the US

1:18:31

each year currently

1:18:33

are unnecessary. What

1:18:36

so we're doing great?

1:18:38

Okay? What does unnecessary mean means?

1:18:42

I don't know for sure, because that was just

1:18:44

a stat taking off their like Antibiotic

1:18:46

resistance general page, But

1:18:48

in general, unnecessary means either

1:18:51

not the right antibiotic for the infection,

1:18:54

or using an antibiotic to treat a non

1:18:56

bacterial infection.

1:18:57

Right, you wouldn't expect ever

1:18:59

to see zero, right, because

1:19:02

if somebody comes in and they have, you

1:19:04

know, some infection but you don't

1:19:06

know what it is yet, or you suspect

1:19:08

it's a bacterial infection, you're going to try different

1:19:10

antibiotics, right, and so that would be included

1:19:13

in that. I'm just trying to wrap my brain around this. Forty

1:19:15

seven million.

1:19:16

Yeah, it's a good question. I don't know if that includes

1:19:18

like every time that you give vanken zosin

1:19:21

in the er, which like everyone

1:19:23

who comes into the ear gets those two antibiotics

1:19:26

at first, right when we don't know what they have yet,

1:19:29

right, So I don't know if that's included

1:19:31

or if that's just prescriptions like outpatient

1:19:33

what you get sent home with. Either

1:19:36

way, it's terrifying. I mean forty seven million.

1:19:38

Oh yeah, so

1:19:42

that's in the US.

1:19:44

Also in the US, it's estimated

1:19:46

that more than and this is very

1:19:48

recent data, so this is from a report that came out

1:19:50

at the end of twenty nineteen. It's

1:19:53

estimated that there are more than two point

1:19:55

eight million antibiotic resistant

1:19:58

infections in the US year

1:20:01

that result in more than

1:20:03

thirty five thousand deaths.

1:20:08

Wow, so thirty five thousand

1:20:10

people a year are dying in the US because of antibiotic

1:20:13

resistant infections.

1:20:14

Do you have global numbers?

1:20:16

Great question. I tried really hard to

1:20:18

get solid global numbers. It is very,

1:20:20

very difficult. So the World Health

1:20:22

Organization has set up in I believe

1:20:25

twenty fifteen, they set up the Global Antimicrobial

1:20:28

Resistance Surveillance System,

1:20:30

which is basically every country

1:20:32

setting up their own surveillance system.

1:20:35

So I think now it's over sixty countries

1:20:38

that are reporting their antimicrobial resistance

1:20:40

data to the World Health Organization, but

1:20:44

they don't seem to aggregate that

1:20:46

data and present it as overall

1:20:48

numbers. Overall, World Health

1:20:51

Organization estimates that in

1:20:53

many parts of the world over forty

1:20:55

percent of bacterial infections

1:20:58

or with bacteria that are resistant to antibiotics.

1:21:01

But I don't have numbers on deaths. I do

1:21:03

have numbers. In the EU.

1:21:07

In twenty fifteen, an estimate

1:21:09

from the European Union was

1:21:11

that six hundred

1:21:14

and seventy one thousand infections

1:21:17

were likely antibiotic resistant

1:21:19

and that likely resulted

1:21:21

in thirty three thousand deaths in twenty

1:21:24

fifteen.

1:21:25

Oh my gosh.

1:21:26

So that's in the EU, but

1:21:29

a lot of the increase in antibiotic

1:21:31

use is in low and middle income

1:21:34

countries, And we don't really have good data

1:21:36

on the number of resistant infections

1:21:40

worldwide. But it's bad, it's

1:21:42

not good. It's a lot.

1:21:44

So I have two questions.

1:21:45

Okay.

1:21:46

The first question is about in the US,

1:21:49

are antibiotic resistant infections

1:21:52

reportable? Like are you required

1:21:54

to report them?

1:21:55

Well, that's a really good question. I don't fully

1:21:57

know the answer to that. So there's this that

1:22:00

report that came out in twenty nineteen has a

1:22:02

list of like the most concerning

1:22:05

pathogens, right, and the World Health Organization

1:22:07

also has a list of what

1:22:09

their pathogens of greatest concern are

1:22:12

and those lists mostly overlap, So

1:22:14

I would think that most of those pathogens

1:22:17

are going to be reportable in the

1:22:19

US. Okay, But that doesn't

1:22:21

mean like every time that, for example,

1:22:24

someone comes in with a UTI, if

1:22:26

you do a urine culture, you might

1:22:28

send that culture off to see

1:22:31

what the resistance profile is,

1:22:34

and that bacteria might be

1:22:36

resistant to a few antibiotics,

1:22:39

So then we use that to choose what antibiotic

1:22:41

we give to that person. But I don't

1:22:43

think that we then report that necessarily

1:22:45

to the CDC. It probably goes

1:22:47

to the local public health district so that we can

1:22:49

keep track of what the general antibiotic

1:22:52

resistance looks like in

1:22:54

our area. Gotcha, So hospitals

1:22:57

keep track of things like that.

1:22:59

Okay.

1:23:00

So I will say that a report that

1:23:02

came out in twenty fourteen, which is

1:23:05

earlier than most of the data I was hoping

1:23:07

to find, estimated that currently

1:23:10

worldwide, there are seven

1:23:13

hundred thousand deaths attributed

1:23:15

to antimicrobial resistance worldwide.

1:23:19

That is a lot.

1:23:21

It's a lot. And they projected

1:23:24

that out and estimated

1:23:26

that by twenty fifty that number

1:23:28

would go up to ten million.

1:23:30

Oh my god, if we

1:23:33

do nothing, like if we just continue on

1:23:35

the same pathway.

1:23:37

Yeah, Oh my

1:23:39

gosh. Yeah. And then

1:23:41

they also estimated what the overall

1:23:43

cost, like the monetary cost of that would

1:23:46

be, that it would

1:23:48

cost the world up to one hundred trillion

1:23:50

dollars antimicrobial resistance.

1:23:53

Yep.

1:23:53

I can't. I can't comprehend that number. Wow.

1:23:58

I was really hoping to find more

1:24:01

recent, like hard data on

1:24:03

anti microbial resistance, and I came

1:24:06

across a paper that came out in twenty sixteen

1:24:08

that really highlighted some of the issues

1:24:11

that we have in even trying to get a handle

1:24:13

on this burden of antibiotic

1:24:15

resistance because

1:24:18

that number, that estimated number

1:24:20

of deaths, like it's such

1:24:23

an estimate. We really don't have

1:24:25

solid numbers on that. Well.

1:24:27

And then I also, you know, my other

1:24:30

question was was about how

1:24:32

do you attribute cause of death exactly?

1:24:35

And so that's yeah, so like if

1:24:37

you're in the hospital and you go in for like

1:24:39

a routine surgery like appendicitis,

1:24:41

and you get MRSA and then you die,

1:24:44

is that MRSA is that appendicitis?

1:24:47

Right? Exactly? That's kind

1:24:49

of exactly what they were highlighting in this paper.

1:24:52

We can't calculate the number

1:24:54

that we really need to calculate to know

1:24:57

the number of deaths attributable

1:24:59

to the fail year of antibiotic therapy

1:25:02

due to antibiotic resistance because

1:25:04

we don't know enough about the

1:25:06

rates of resistance or the rates of

1:25:08

infection for so many different infections.

1:25:11

You have so many things like diarrhea

1:25:13

that can be caused by so many different pathogens.

1:25:16

So like, yeah, right, it's

1:25:19

a really complicated, big

1:25:21

picture.

1:25:22

Question, but there is no

1:25:24

question that it is leading

1:25:26

to death. And it's

1:25:29

horrible.

1:25:29

Yeah, it really is, and it's a very

1:25:31

multifactorial problem. Like

1:25:34

you mentioned, Aaron, there's a number of different

1:25:36

factors contributing to this, right, inappropriate

1:25:38

prescriptions, misuse of

1:25:41

taking those antibiotic prescriptions,

1:25:43

agriculture, poor sanitation in hospitals.

1:25:46

So I will say that all of the kind

1:25:48

of action plans that CDC

1:25:50

and WHO and all these different organizations,

1:25:53

they're very holistic plans,

1:25:55

right. They recognize that this is not going

1:25:58

to be solved by just one change

1:26:00

or even a few changes. It's a whole

1:26:03

bunch of different solutions

1:26:05

that are going to be required for this problem.

1:26:08

But one thing that it's definitely going to take

1:26:11

are new methods of treatment because

1:26:14

for many pathogens, resistance is already

1:26:16

here. So we need new ways to target

1:26:19

these pathogenic bacteria. We

1:26:21

do, and this is where we'll have some

1:26:23

shining moments of hope. Okay, yay.

1:26:27

The good news is there are so many

1:26:30

people working on the issue of antibiotic

1:26:32

resistance from a treatment standpoint.

1:26:35

You heard in our last Antibiotics episode

1:26:37

about a group that's working on new methods

1:26:39

of identifying antibiotic compounds

1:26:41

using machine learning, which

1:26:43

is so cool. I love

1:26:45

it so much.

1:26:46

It's amazing. It's literally unbelievable,

1:26:49

so cool.

1:26:50

There are a number of other groups

1:26:52

working on alternative therapy strategies

1:26:55

as well. There's some really promising data

1:26:57

on probiotic therapy, which I think

1:26:59

is awesome. So basically boosting

1:27:02

gut microbiomes to try and both

1:27:04

treat and prevent toxic infections.

1:27:07

Fecal transplants, fical transplants.

1:27:09

So probiotic therapy is a very cool

1:27:12

I feel like we'll probably talk a lot more about that

1:27:14

in a Microbiome episode.

1:27:16

But you should definitely google fecal transplant.

1:27:19

Oh for sure, it's so cool. There's

1:27:22

also a lot of work being done on

1:27:24

combination therapy, so whether

1:27:27

that's combinations of an

1:27:29

antibiotic and another molecule

1:27:31

that blocks a normal resistance mechanism

1:27:33

to that antibiotic, like

1:27:36

augmentin that was an example I gave early

1:27:38

on, or whether it's

1:27:40

giving a number of different antibiotics

1:27:42

in combination that have different mechanisms

1:27:44

of action, which is how we already treat

1:27:46

things like tuberculosis for example.

1:27:49

Right which by the way, I

1:27:51

know we touched on this in the tuberculosis episode,

1:27:53

but like multi drug

1:27:56

or extremely druggers is in tuberculosis is terrifying

1:27:58

aarin tubercula.

1:28:00

Yes, this is so terrifying that it's not even included

1:28:02

on the lists of the terrifying bacteria

1:28:04

because it's like its whole own version. Like

1:28:07

we've known about resistance in TV

1:28:09

for so long, like we don't even need to include it

1:28:11

on our list.

1:28:12

Oh gosh, the escape list.

1:28:14

Is that what you're talking about.

1:28:15

Yeah, I didn't even mention the names of any of them,

1:28:17

but I

1:28:20

got ahead of myself. So

1:28:23

some of those pathogens include

1:28:25

Enterococcus, feceum,

1:28:28

staph aureus, club Ciella,

1:28:30

Assinitobacter balmani i, Pseudomonis,

1:28:33

and Enterobacter. Those

1:28:35

are the six that are really commonly

1:28:39

like the big escape I

1:28:41

think, just because they make a nice acronym. But

1:28:43

there's really at least twelve that

1:28:46

we need to be concerned about.

1:28:49

But we don't. We don't care about the other six just

1:28:51

because they don't make a good act.

1:28:52

They don't make a good acronym. H. Pylori,

1:28:54

lah, camplobacteror Gonorrhea,

1:28:58

Salmonella, strep. New.

1:29:00

You know, there aren't enough vowels

1:29:02

in there.

1:29:03

I know that's why they're not included.

1:29:05

We do care about all of those.

1:29:07

Oh it's especially gonorrhea, man,

1:29:10

Oh my gosh. Yeah, So

1:29:13

there's a lot. There's

1:29:15

also a lot of work being done on antimicrobial

1:29:18

peptides. There's work being

1:29:20

done on stimulating the immune

1:29:23

response and using our own immune

1:29:25

system to better fight off infection. There's

1:29:29

the use of things like iron scavenging

1:29:32

molecules. One

1:29:34

of the coolest areas and one

1:29:36

that I've been most excited to talk about

1:29:39

for a while now, is phage

1:29:41

therapy.

1:29:42

Phage therapy. We briefly

1:29:44

touched on it in the MRSA

1:29:47

episode, very briefly, very

1:29:49

briefly, too briefly, far too briefly.

1:29:51

And so who better to tell you

1:29:54

about the status of phage

1:29:56

therapy research than

1:29:59

the provider of our first hand account who

1:30:01

literally treated her own husband with phage

1:30:03

therapy and also studies it, doctor

1:30:07

Stephanie Strathty. Well,

1:30:10

thank you so much for taking time out of your day to

1:30:12

chat with us. We're really excited about this episode

1:30:15

and thrilled to get the chance to talk to you. We'd

1:30:18

love for you to kind of give us first maybe

1:30:20

a brief overview of like what phage

1:30:23

therapy is for our listeners and kind

1:30:25

of how it works sure.

1:30:27

Well. Phages are viruses

1:30:29

that have naturally evolved to attack bacteria.

1:30:32

They're like the perfect predator for bacteria.

1:30:35

They've actually co evolved for four

1:30:37

billion years. They're the oldest

1:30:39

and most ubiquitous organism on the

1:30:42

planet. And it's thought that there's about ten

1:30:44

million trillion trillion. That's

1:30:47

ten to the power of thirty one for you

1:30:50

numeric matthew people out there. And

1:30:52

so they're everywhere. They're on

1:30:54

our skin, they're in our guts, we

1:30:56

poop them out. They're in water. You

1:30:59

know, a single drop of water can have trillions

1:31:01

of phages in it. We just haven't been able

1:31:04

to understand what they're like

1:31:06

because they're so small. They're about one hundred

1:31:08

times smaller than bacteria. And

1:31:11

they were discovered in nineteen

1:31:14

seventeen by a French

1:31:16

Canadian named Felixe de Caral,

1:31:19

and you know, he deduced that these

1:31:22

must be viruses that are parasites

1:31:24

of bacteria, even though you couldn't

1:31:26

see them until the electron microscope

1:31:28

was developed in the early nineteen forties,

1:31:31

and people actually had a big debate

1:31:33

as to whether or not these were proteins or

1:31:35

whether they were viruses or whatever. And

1:31:38

Deharel himself was quite a character.

1:31:42

He was very egotistical, he wasn't formally

1:31:44

trained, and he was really pushed

1:31:46

to the margins of society and

1:31:49

the medical field. And then

1:31:51

when he helped the former Soviet

1:31:54

Union developed the first

1:31:56

page therapy center in the world, it

1:31:58

got the label, as you know, Soviet

1:32:00

science, and this was around World War Two,

1:32:02

and of course that led to a big geopolitical

1:32:05

bias of like pink O Komi science,

1:32:08

and that put a cloud

1:32:10

over phage therapy for decades,

1:32:12

and so that's one of the reasons why the

1:32:14

West really abandoned it. And of course penicillin

1:32:17

came on the scene in nineteen

1:32:19

forty two. Even though it was discovered

1:32:22

in nineteen twenty eight, it had been you know,

1:32:25

it took some time to come to end

1:32:27

too the field, and that was because it

1:32:29

was needed on the warfront. And so people

1:32:31

thought antibiotics are wonder drugs, and of

1:32:33

course they were for a while. But

1:32:36

anti mycrobia resistance has just continued

1:32:38

to outpace us, and nobody's really

1:32:41

been paying attention to that until

1:32:43

you know, we get these people who are

1:32:46

having you know, minor scrapes or surgeries,

1:32:48

and we realized, oh my gosh, they got

1:32:50

a superbug and there's nothing left to kill

1:32:52

it anymore.

1:32:54

Could you talk us through what a typical

1:32:56

course of phage therapy might look like.

1:32:59

So how do you even go about finding the

1:33:01

right phages and then administering them.

1:33:04

Well, the thing about phages that's both

1:33:06

a blessing and a curse is that they're really finicky.

1:33:10

They only matched to specific

1:33:12

bacteria. So for an

1:33:14

organism like Staphylococcus, which

1:33:17

you know, one of the strains is mursa

1:33:20

right at the silin resistant staph wreas

1:33:22

that's the superbug that was discovered

1:33:24

first, maybe about twenty to thirty

1:33:27

phages will cover the majority

1:33:29

of circulating strains around

1:33:31

the world, And that's pretty good

1:33:34

because you don't need that many of them, and maybe you

1:33:36

could have like a cocktail of phages that would

1:33:38

you know, cover the majority of those infections.

1:33:41

But for superbugs like Tom's asked

1:33:43

me to back to Bomanii, it's

1:33:46

very very specific. So the phage

1:33:50

not doesn't just have to

1:33:52

match the genus and the species, it has

1:33:54

to match the isolate so Tom's

1:33:57

bacteria. So that means

1:33:59

you have to like essentially look for a

1:34:01

needle in a haystack. But it's a

1:34:04

little worse than that because when you think about

1:34:06

where there's a lot of bacteria, that's

1:34:08

where you're going to find a lot of phages. So

1:34:10

if you need to go on a phage hunt, you

1:34:13

have to go to some of the worst places

1:34:15

around. And we're talking like sewage,

1:34:19

barnyard, waist, scummy

1:34:21

ponds, that kind of thing. So the

1:34:23

phages that were actually used to

1:34:25

treat tom we're from. So I can

1:34:28

say literally that my husband is full

1:34:30

of I mean, who can get to say

1:34:32

that to their husband?

1:34:37

That's amazing.

1:34:38

And then so what then once you if

1:34:40

you go in and you dig through all

1:34:42

that sewage and you get lucky enough you find

1:34:44

that needle in the massive, massive haystack,

1:34:47

do you then take that to the lab culture

1:34:49

it?

1:34:49

And then what's the next step after that? How

1:34:51

do you actually get it into that person?

1:34:54

Well, the old fashioned plaque

1:34:57

assay and it's actually this is

1:34:59

something that's high school and

1:35:02

freshmen learn how to do you

1:35:05

have a Petrie dish, say with your bacterial

1:35:08

lawn or your bacteria streaked

1:35:10

on it, and if you want to see that if

1:35:12

you have phages that are matching to that

1:35:15

bacteria. You put a drop of sewage

1:35:17

on the petrie dish and you incubate it for twenty

1:35:19

four to forty eight hours, and if it comes

1:35:22

back looking like a little like Swiss cheese

1:35:24

because there's holes literally in

1:35:26

the petrie dish, you get really excited

1:35:28

because even though you can't see the phage, because

1:35:31

they're smaller than the naked eye and even

1:35:33

smaller than the light microscope can detect,

1:35:36

you know that they've been at work because they've

1:35:38

gobbled up a bacterial colony there. So

1:35:41

then you can pluck it out and add

1:35:43

it to more bacterial suspension, and

1:35:45

then you need to purify it, and that's the tricky

1:35:47

part. There's different techniques to purify

1:35:50

phage suspension, but if you're

1:35:53

going to treat it with phage intravenously,

1:35:56

you want to get it as pure as possible because

1:35:58

if there's a lot of bacteria debris

1:36:00

and the suspension, it could elicit

1:36:02

septic shock and the patient and could kill them.

1:36:05

And that's what we're worried about with Tom's

1:36:07

situation, and nobody really knew

1:36:09

what the threshold for safety was, so we

1:36:11

were taking a big risk.

1:36:14

Yeah, so you

1:36:16

mentioned kind of how difficult it is to

1:36:18

even be able to identify and find

1:36:21

these phases, especially when you're dealing with bacteria

1:36:24

where you maybe only have like have to

1:36:26

find a very specific phage. So could

1:36:28

you talk maybe a little more broadly about some of

1:36:30

the pros and cons of using

1:36:33

phage therapy, maybe in like comparing

1:36:35

and contrasting that to antibiotics that

1:36:37

we have currently.

1:36:39

Yeah, Well, the good news about phages

1:36:42

is that again there's ten million, trillion trillion

1:36:44

phages on the planet, so there's almost an exhaustible

1:36:47

supply of them. It's just you need to find

1:36:49

the right phages to match the bacteria

1:36:52

that you want to kill. So if you have

1:36:54

to go back to sewage or you know, barnyard

1:36:57

waste or whatever every single time you

1:36:59

need to treat somebody, that would be a real pain.

1:37:02

And obviously it's very labor

1:37:04

intensive and you may not find phages

1:37:06

in time, and we've been in that situation with

1:37:08

other patients. But if you have a

1:37:11

phage library or a phage bank that's

1:37:13

essentially like a walking and cooler,

1:37:15

where you have thousands of phages and

1:37:18

they're already identified and characterized

1:37:20

and sequenced, then you could just kind

1:37:22

of go in there and you

1:37:24

know, see if the bacteria that you want to kill

1:37:27

has phages in the library. So that's

1:37:30

that problem about how do you

1:37:32

find the phages to match the bacteria

1:37:34

that you want to kill? Can be overcome, gotcha.

1:37:38

So one of the questions I had was about

1:37:41

dose and sort of one of the negative

1:37:44

consequences of or potential consequences

1:37:46

of phages, so like, how do

1:37:48

you know how much how

1:37:51

many phages to give? And also

1:37:54

when those phages break apart those

1:37:56

bacterial cells, what are some of the risks

1:37:58

associated with that.

1:38:01

Well, to be honest, nobody really knows

1:38:03

the right dose for phages in

1:38:06

most cases, and that's

1:38:09

part of the translational basic science

1:38:11

research that needs to go on so

1:38:13

that we can, you know, get ready for clinical

1:38:16

trials. In Tom's case, we

1:38:19

just you know, took an estimate

1:38:21

based on his weight and the fact that

1:38:23

he had a systemic infection where you

1:38:25

know, the bacteria were in every

1:38:27

cavity in his body. And we

1:38:29

knew that if you underdose, if you

1:38:32

give too few phages, the body's

1:38:34

own immune system can eliminate them and

1:38:36

the phages might not ever reach their target.

1:38:39

And we thought, well, is there a risk

1:38:41

of overdosing him or whoever

1:38:44

you're treating, And we talked to experts

1:38:46

and they said, you know, we haven't actually,

1:38:48

you know, seen any side effects

1:38:51

of this as long as the endotoxin,

1:38:53

which is essentially the bacterial debris that

1:38:56

is caused when you are growing up

1:38:58

a lot of phage. In the context

1:39:01

of a lot of bacteria that endotoxin, there's

1:39:03

a lot of antidoxin left that could

1:39:05

kill the person. So again,

1:39:08

we haven't seen that though we've treated over

1:39:11

a dozen patients and

1:39:14

you see San Diego and dozens other

1:39:16

internationally.

1:39:17

Gotcha. Yeah, So you

1:39:20

talked a little bit about some of these challenges moving

1:39:22

forward with phage therapy, but let's

1:39:25

talk about the bright future. So since

1:39:27

the publication of your book, there's been

1:39:29

a lot of forward progress in phage

1:39:31

therapy and in new initiatives,

1:39:34

and so can you talk a little bit about what you see

1:39:36

as the future for phage therapy

1:39:38

and also are there going

1:39:40

to be genetically engineered phages

1:39:43

for specific infections.

1:39:46

Well, yes, there's been a lot of really exciting

1:39:49

developments since then. The first

1:39:51

is that the first genetically

1:39:53

modified phage cocktail to be used

1:39:56

successfully to treat a human Bacterial

1:39:59

Infection was published in May

1:40:02

of twenty nineteen, so a

1:40:04

year ago from now, and it was

1:40:06

an incredible case, just as fantastic

1:40:09

as Tom's. This is a young girl,

1:40:11

her name's Isabelle. I happen to

1:40:13

know her now through our connections

1:40:16

and Facebook and social media. She

1:40:19

had a hassistic fibrosis and she'd

1:40:21

had a double lung transplant and

1:40:24

had acquired this what's called Microbacterium

1:40:27

obsessis. And people who are familiar

1:40:29

with tuberculosis will know that michael

1:40:32

Bacterium tuberculosis, a

1:40:34

cousin to this Microbacterium obsessis,

1:40:36

is the biggest bacterial killer

1:40:38

in the world. It almost kills two million

1:40:40

people per year. And so this

1:40:43

is a very difficult to treat

1:40:46

pathogen. And she was literally

1:40:48

dying. She was in hospice and her mother heard

1:40:50

about Tom's case contacted

1:40:52

her doctor. The doctor contacted some

1:40:55

of our colleagues, and we

1:40:58

happened to know that there was a named

1:41:01

Graham Hatful at the University of Pittsburgh

1:41:03

who runs this wonderful training program called

1:41:05

Sea Phages that teaches

1:41:08

students how to find phages, and essentially

1:41:10

they're doing this page hunt that

1:41:12

I described earlier, and

1:41:14

all of the phages that they find go into a giant

1:41:17

phage bank, and they have about

1:41:19

fifteen thousand Mycobacterium phages.

1:41:21

They'd never even dreamed that they could be used

1:41:23

therapeutically, and when

1:41:26

asked, they said, wow, we'll certainly

1:41:28

see if any of our phages will be a match

1:41:30

for Isabella's bacteria. And

1:41:33

three of them were, and one was perfect.

1:41:36

Its name was Muddy. It

1:41:38

was found on a rotting egg plant

1:41:40

from South Africa by a student there.

1:41:43

And all the students who

1:41:45

find new phages get to name them, right, that's

1:41:48

part of the bonus. And two

1:41:50

of the other phages were the sleepy kind.

1:41:52

In our book, I described them as hitting

1:41:55

this snooze button. They actually don't kill the bacterial

1:41:57

cell, but that's all they could find. What

1:42:00

they did was they genetically manipulated

1:42:02

those two phages by clipping out

1:42:05

the repressor gene in a technique

1:42:07

called we're commineering, which is, you

1:42:09

know, a prequel to a crisper

1:42:12

gene editing, and it

1:42:14

forced those sleepy phages to become

1:42:17

the phage rage kind of phages that actually

1:42:19

kill the bacterial cell. And then

1:42:21

they had to convince the UK government where

1:42:24

she was living in the UK, that

1:42:27

this was okay to use, and luckily

1:42:29

they went along with it because they said, well, it's

1:42:31

not a GMO because you took

1:42:33

away a gene, you didn't add a gene. And

1:42:37

Isabelle received phage

1:42:39

therapy intravenously because based

1:42:42

on Trum's protocol, we convinced them

1:42:44

that it was safe. She left the

1:42:46

hospital within a week. It

1:42:49

was just stunning, and she's made a

1:42:52

great recovery. She's I believe

1:42:54

she's still receiving phage therapy now, but

1:42:57

she's you know, working, She's finished

1:42:59

her A level exam, she's learned to drive a car.

1:43:02

You know, she's dyed her hair purple. You

1:43:04

know, she's, like, I believe she's

1:43:06

eighteen now and she's doing great. So

1:43:09

that case is a landmark

1:43:11

because that's the first time that genetically

1:43:15

engineered phage has been used to treat a

1:43:18

bacterial infection and a human being

1:43:20

successfully. And also it's the first

1:43:22

time that a Mycobacterium infection

1:43:24

and a human has been successfully

1:43:27

treated with PAGE therapy. And Len's

1:43:29

hope that maybe someday we could treat

1:43:32

tuberculosis with PAGE therapy. Wouldn't

1:43:34