Antibiotic Resistance: How Humans Ruined Miracle Drugs

Antibiotic resistance is possibly the biggest existential threat to humanity. What were the causes, how does it work, and what do we do about it?

☠️NONE OF THE INFORMATION IN THIS VIDEO SHOULD BE USED AS MEDICAL ADVICE OR OPINION. IT IS FOR GENERAL EDUCATION AND ENTERTAINMENT☠️

🔗 L I N K S 🔗
📱Instagram: https://www.instagram.com/patkellyteaches/
💰Patreon: https://www.patreon.com/corporis
📚My favorite books https://docs.google.com/document/d/1wuG-8EiF2lMbFdEG-9k1qi1d1KZAdGK1o41o7SYed_k/edit?usp=sharing

🔑 P A T R O N S 🔑
Joanne K
Sal F.
Ansel K
Anton
Brandon K
Pranav M
Paul
Brendan P
Dane M
Kristoffer R
Jakub V
Joe B
Karly N
Mindi F
Drake W
Kathy K
Mike W
Hyeon-Seo
Jacob S.
Robin B
Robb W
Sarah B
Carl
Dontae W
Karen S
Michael R
Brian H
Jonathan G
Brian T
Thelma S
Silverstar
Brian B
Michael G
Zoe C

📜 S O U R C E S 📜
Annotated script found here: https://www.patreon.com/posts/antibiotic-video-95558251

[Affiliate links] I get a commission if you decide to buy it through this link.
Miracle Cure, the Creation of Antibiotics by William Rosen

Big Chicken by Maryn McKenna

Antibiotic Discovery and Resistance: The Chase and the Race (2022) https://pubmed.ncbi.nlm.nih.gov/35203785/
*THIS ONE WAS GREAT* Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects (2021) https://www.sciencedirect.com/science/article/pii/S1876034121003403#bib0115
The antibiotic resistance crisis, with a focus on the United States (2017)
https://www.nature.com/articles/ja201730
Origins and Evolution of Antibiotic Resistance (2010) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937522/
WHO Fact Sheet https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
FDA Fact Sheet https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/antimicrobial-resistance-information-fda
CDC Fact Sheet https://www.cdc.gov/drugresistance/about.html
CDC 2019 AMR report https://www.cdc.gov/drugresistance/biggest-threats.html
The evolving response to antibiotic resistance (1945–2018)
https://www.nature.com/articles/s41599-018-0181-x

Chain & Abraham Penicillinase (1940) https://www.nature.com/articles/146837a0
1945 Fleming Nobel Prize speech https://www.nobelprize.org/uploads/2018/06/fleming-lecture.pdf
Ampicillin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080027/
Methicillin trial in BMJ (1960) https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2097972&blobtype=pdf
Carbapanems https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195018/
Evolution of B-lactamase inhibitors (1991) https://www.jstor.org/stable/pdf/4456082.pdf

Animal Protein Factor by Jukes et al (1949) CC BY 4.0 DEED
https://www.sciencedirect.com/science/article/pii/S0021925818566837
ON THE MECHANISM OF THE DEVELOPMENT OF MULTIPLE DRUG-RESISTANT CLONES OF SHIGELLA (1960) https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1348-0421.1960.tb00170.x
Swann Report (1969) https://wellcomecollection.org/works/cqvewh54
A Review of Antibiotic Use in Food Animals: Perspective, Policy, and Potential (2012) https://journals.sagepub.com/doi/pdf/10.1177/003335491212700103
Pharming animals: a global history of antibiotics in food production https://www.nature.com/articles/s41599-018-0152-2
Staphylococcal Infection in Meat Animals and Meat Workers, Ravenholt (1961) https://www.jstor.org/stable/4591310

Study on genetic engineering of Acremonium chrysogenum, the cephalosporin C producer (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640796/
A Glimpse of the early history of the cephalosporins (1979) https://www.jstor.org/stable/pdf/4452284.pdf
Celbenin resistant Staph (original MRSA paper – 1961) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952888/pdf/brmedj02876-0102b.pdf
MRSA in Boston City Hospital (1968) https://www.nejm.org/doi/10.1056/NEJM196808292790901?url_ver=Z39.88-2003
Five decades of MRSA https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61566-3/fulltext
Carbapnems: Past, Present, and Future https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195018/
Thienamycin to Imipenem (1983) https://academic.oup.com/jac/article-abstract/12/suppl_D/1/773528?redirectedFrom=fulltext&login=false

FDA GFIs https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry
GDI 213 FDA Document https://www.fda.gov/media/83488/download
Use of Ichip for High-Throughput In Situ Cultivation of “Uncultivable” Microbial Species (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849220/
Discovery of teixobaxtin (2015) https://www.nature.com/articles/nature14098

💻 C O N T A C T 💻
If you’d like to sponsor a video or have other business inquiries:
patkellyteaches [at] gmail.com

⌛T I M E S T A M P S ⌛
0:00 Intro
0:58 Biology of Antibiotic Resistance
5:51 Human Use
16:24 Agriculture
26:41 Solutions

In February 2014, the American quick-service chain Chick-Fil-A made a promise: by 2019 they would only serve chicken raised without antibiotics. Panera Bread and Chipotle had already made similar promises, but Chik Fil A was such a big company that this represented something bigger for the entire industry.

While the decision was marketed as a way of making the food more natural the overall trend throughout the industry came from greater worries about antibiotic resistance, especially from agriculture. Throughout the twenty-teens, public health institutions ranging from the World Health Organization, to America’s CDC were warning about bacteria that weren’t affected by

The antibiotics we typically used to treat them. Which meant that after benefitting from antibiotics for the last 80 years, resistance threatened to bring humanity back to a time when a simple cut could become life threatening.

So for this video, I wanted to learn two things: one, how did we get into this mess, what were the causes? And two, what are some of the solutions that aren’t just, more antibiotics? You see the run time. This one is gonna be packed. Grab a snack.

Antimicrobial resistance, or AMR, is when germs like bacteria, viruses, or fungi no longer respond to the drugs designed to kill them. Infections with resistant germs are harder to treat and sometimes fatal. Also, I’m saying antimicrobial here because we’re not just talking about bacteria which

Are treated by antibiotics — this problem has been observed in all kinds of germs that make humans sick. But yes, for the most part, we’re talking about antibiotics. Alright, how does it work? Well, high level antimicrobials kill germs that are susceptible to that drug. But not every antibiotic kills every bacteria.

Sometimes, there are germs that have some kind of trait, or resistance mechanism, that allow them to survive the drug. The germs that survived multiply and share these traits with their offspring, which create a new strain of germs that shares the resistance mechanism.

In this way, antibiotics apply something called selective pressure — they make it more likely that bacteria with certain traits survive — in this case we’re selecting traits for resistance. And there are four big groups of traits they can develop.

First, bacteria can change their permeability which can limit how the drug gets into the cell. That’s because of these little Mario looking pipes called porins. The bacteria can mutate and make more or less porins, or make a different kind of porin that lets in different materials.

This is especially relevant to Gram negative bacteria, which have cell membranes on both sides of the cell walls. Like certain Enterobacteria have become resistant to carbapenem antibiotics by lowering the number of porins on their cell membrane. Second, they can physically remove the antibiotic through efflux pumps, little pores on the

Cell membrane that clear out the antibiotic more quickly. Sometimes they efflux one drug specifically, but sometimes they can clear multiple, unrelated drugs. There are lots of types of efflux pumps. Next, bacteria can modify the antibiotic’s target, which covers a lot of different mechanisms,

But fundamentally you can think of them like locks and keys. For example, penicillin works by binding to an enzyme called transpeptidase, an enzyme that lets bacteria link their cell walls together. Penicillin is the key, transpeptidase is the lock that this key works on.

But if a bacteria tweaks its transpeptidase, that affects how well penicillin can bind to it and thus, how well they can work. Modifying the drug target is like changing the lock. But the fourth and final strategy involves breaking the key itself. Bacteria can develop enzymes that change or destroy the antibiotic.

For instance, a bunch of pathogens can make enzymes that break down penicillin; it’s a type of enzyme called penicillinase. -Ase just indicates that it’s an enzyme. In this case, the lock is the same, but the bacteria broke the key. Penicillinase has actually been around since before humans used penicillin.

But by introducing the antibiotic, humans helped speed up the development of new penicillin-resistant bacteria. We selected for it. But how do whole strains of bacteria develop these traits? Well, there are two major paths here. There’s intrinsic resistance, which has a few different definitions, but for this

Video, it’s when an antibiotic wouldn’t work against a germ anyway, regardless of previous exposure to that antibiotic. For example, glycopeptides won’t work against Gram negative bacteria since the drug is just too big to cross their cell membrane. The other, more worrying path is acquired resistance, which happens in a couple different ways.

See just like our cells, bacteria divide and replicate, and when they do, there’s a chance that their DNA mutates. And sometimes, that mutation gives it a resistance mechanism. For this animation, the gene for a resistance mechanism will be in red.

The gene can be inherited from parent to offspring, or it can be acquired through through mobile genetic elements — this is when germs give resistance genes to other existing germs. And it’s not limited to the same type of bacteria either. They can actually share across groups.

And there are a few ways to do this. There’s conjugation which is when two cells butt up next to each other and share DNA directly between them. There’s transformation where cells pick up free-floating pieces of genetic material, and there’s transduction where resistance genes are carried by viruses.

But the sharing method that gets the most attention is transformation through plasmids. These things are little circular discs of DNA that can carry code for all kinds of traits, including resistance mechanisms, and they can be shared from cell to cell. I imagine them like burned CDs from the early 2000s.

Like, you could burn a My Chemical Romance album onto a CD, give it to your friend so they could download the song onto their computer, then keep burning CDs to give to more friends. And just like burned CDs, they can have one song or many.

They can code for one resistance mechanism or several. One of the reviews I read warned that bacteria that form biofilms may be particularly good at sharing genes. These biofilms create a protective layer against drugs and the host’s immune cells.

And since the cells are all clumped together, it may be easier for them to do horizontal gene transfer. So with that little crash course, now we can get into the story, which really starts thanks to two things happening in parallel: overuse of antibiotics in humans and overuse in agriculture.

And before we get too far, I actually want to shout out two books that helped me make sense of the story: The Miracle Cure by William Rosen, and Big Chicken by Maryn Mckenna. I’ll leave links to both of them in the description. You’ll love both of them.

Now you might think that the story of resistance starts after antibiotics had been on the market for a few years, but it actually starts before penicillin even came out. One of the first documented inklings of resistance came from a strain of Strep pyogenes in a military hospital in the late 1930s.

And that’s the trend for the first part of the story — resistance sprung up in hospitals, where people were using antibiotics. Then in the 40s, two of those Oxford scientists who worked on penicillin production, Ernst Chain and Edward Abraham, documented a strain of E. coli that produces penicillinase.

This was before they even had any evidence that penicillin would work in humans. Chain later found a strain of Staphylococcus aureus that could make penicillinase as well. And it only took a few years before it became common outside the lab.

In 1945, a study from Australia measured the penicillin resistance of over a hundred strains of Staph — some of which were collected from hospitals that hadn’t used penicillin yet, and some from hospitals that had. They found that only the strains collected after penicillin was released were resistant to the drug.

Around the same time, a hospital in Britain started keeping track of staphylococci that produced penicillinase. It only took 5 years for the prevalence of penicillinase-producing staph to grow from 8% to 60%. Other scientists started to raise some red flags too. Like René Dubos, the French scientist who found gramicidin, he advised his students

Not to use antibiotics too much. But this was more of a warning, it wasn’t quite an emergency yet. Alexander Fleming, the Scottish scientist who identified the antibacterial effect of penicillin, weighed in as well. He worried that germs could develop resistance if exposed to tiny amounts of antibiotics.

He rather famously talked about it in his Nobel Prize speech. He said “There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant”.

Fleming was describing the main issue in the middle of the medical discourse at the time — we’ve got these great tools to beat infection, but we have to balance individual benefit with public health. They knew that these drugs had the potential to save lives, but individual users could

Get the collective into more trouble. Fleming delivered that speech in December 1945, the same year that penicillin became available over the counter in the US. But it pretty quickly went back to prescription only. Not because of fears of antibiotic resistance, but because people started reporting more cases of penicillin allergies.

Which brings to the first big cause of resistance: humans started using antibiotics. Now, going into this video, I thought the cause was going to be overprescription by doctors, but I couldn’t actually find data to support that. I expected to find data that said doctors prescribed this many units of antibiotics

Per person in 1950, then this much in 1955 and so on. But I couldn’t find it. As far as I could tell, global efforts to track that data started in earnest in the 1980s when we knew resistance was a big deal already.

Instead, the problem was more likely misuse: like when doctors administered antibiotics without knowing if the underlying infection would respond to it, or when patients pressured doctors into giving them antibiotics even when it wasn’t necessary. And there were a handful of companies that added penicillin to everything, which didn’t help.

But definitionally, prescribing any amount of new antibiotic is going to select for bacteria that are resistant to that antibiotic. So it’s no surprise that Penicillin resistant germs started popping up more often during the 1950s. But if we put ourselves in the shoes of folks back then, this all probably didn’t seem

Like an emergency yet because scientists were still discovering all kinds of new antibiotic platforms. Unfortunately, each new antibiotic was the first step in a disappointing and predictable cycle: A new drug was released to the public, using it provided a selective pressure for resistant bacteria.

Doctors saw infections with bacteria resistant to that new drug. And as a result, scientists looked for better versions of that kind of drug. When they found one, the cycle continued again. For instance, the tetracyclines really rolled out in the early 1950s, and by 1959, tetracycline-resistant Shigella had been documented.

Erythromycin came out in 1953. By 1968, someone found Erythromycin-resistant Strep. In 1958, a promising new antibiotic called vancomycin came out, the first in class of glycopeptide antibiotics. And it held out an impressive 30 years before a strain of enterococci developed resistance. All of this meant that we’d need to keep finding new drugs.

But to save you from a dozen overlapping and repetitive stories, I’m going to focus on the most frequently prescribed group of antibiotics — the beta lactams. Now, up until this point, if you wanted a new antibiotic, you’d have to find it in nature.

For example, in 1945, an Italian academic named Giuseppi Brotzu was hanging out on the island of Sardinia, off the west coast of Italy, and started looking for antibiotic-producing microbes of his own. Not on mold like Fleming, and not in soil samples like Waksman, but in sewage.

Brotzu eventually found a microbe that he called Cephalosporium acremonium, which, as you could probably guess from the name, produced an antibiotic called cephalosporin. It took a few years to figure out that it was a beta-lactam drug too, but one that was less affected by penicillinases, which made it a good tool against penicillin-resistant

Bacteria. The Cephalosporins didn’t come out for clinical use until the 1950s, at which point scientists learned that it also had a broader spectrum than original penicillin — you could use them against Gram positive and Gram negative bacteria. Plus, they had fewer adverse reactions than penicillin.

So that was one option: you could find new antibiotics in nature. But one of your other strategies was chemistry. Scientists could make semi synthetic versions of existing antibiotics by starting with a natural antibiotic, and tweaking it into new drugs.

In 1959, penicillin was tweaked into the semi-synthetic celbenin, with the hopes the new drug would work against Staph resistant to penicillin. You probably know this drug as methicillin. At the same time, scientists were working on Ampicillin, but it didn’t hit the market until 1961. Then amoxicillin, which came out in 1974.

And both of these had a broader spectrum than original benzyl-penicillin, which was a plus. In 1960, an article came out in the British Medical Journal that compared the activity of this new celbenin to a bunch of other penicillin varietals. The article was optimistic — this drug worked against Staph that made penicillinase. Awesome.

Unfortunately, it wasn’t even a full year before those hopes were dashed. In 1960, doctors in the UK noticed that a particular strain of Staphylococcus aureus was no longer responding to methicillin. And in 1961, Patricia Jevons from the Staphylococcus Reference Lab in London wrote a letter in

The British Medical Journal describing this strain in detail. This was the first published description of MRSA, methicillin resistant Staphylococcus aureus. Scientists argued how big of a deal this thing would be, with some thinking the strain worked by cranking out a ton of penicillinase.

Like maybe it just overpowered methicillin’s penicillinase resistance and if we threw high dosage cephalosporin at it, everything would be fine. Viewers: it was not fine. It turned out that methicillin-resistant staph had a totally different resistance mechanism than the penicillinase, which meant we didn’t have a tool against it yet.

MRSA stayed on public health radar throughout the 60s, with Denmark experiencing high proportions of resistant Staph starting in 1967. Then in 1968 doctors found a case at a hospital in Boston. This grew into a full fledged outbreak reported in the New England Journal of Medicine.

Staph can live on all kinds of surfaces, including hands. So for the next few decades, MRSA outbreaks clustered around hospitals, and in people who had some kind of contact with hospitals. But then people started getting MRSA who hadn’t been to a hospital. This was called community-associated MRSA.

Thanks in part to the spread of MRSA, and the fact that it’s just not as effective as other beta lactams, methicillin is no longer used in humans And making matters worse, MRSA came at a time when we were starting to see the pipeline of antibiotics dry up.

And one of the factors complicating this was multi-drug resistance — at this point, we’d also learned that bacteria could be resistant to multiple drugs at the same time. This was so concerning because if a bug didn’t respond to penicillin in the past, a doctor might try tetracycline or cephalosporin.

But now we had strains of Salmonella that didn’t respond to any of the usual drugs. So scientists would have to get creative. And one of the most effective strategies was: “what if we try two antibiotics at the same time?”. Scientists knew that something about those semi-synthetic beta lactams affected the bacteria’s penicillinase.

So scientists started using combinations of penicillins on resistant bacteria and found that they were more effective than a single antibiotic. Like one research group gave Ampicillin and Cloxacillin to a bunch of ampicillin-resistant E coli, and it killed way more of the bacteria than Ampicillin alone.

This kind of treatment didn’t work for every penicillin-resistant bug out there, but it got scientists interested in using beta-lactamase inhibitors. Basically, they’d inhibit the penicillin inhibitor. So in 1967, a company called Beecham Pharmaceuticals started screening microbes for these kinds of inhibitors.

They’d put penicillin in a petri dish along with a strain of bacteria that made beta-lactamase, then add in their test microbes and incubate them overnight. If the microbe-of-interest produced beta-lactamase inhibitor, they’d see bacteria-free zones around the sample. It’s the whole rings of inhibition thing we’ve been talking about for the whole series now.

Using this screening process, a group of researchers published their findings that a Streptomyces microbe created a substance called olivanic acid which countered penicillinase-producing pathogens. Clinical tests afterwards showed that olivanic acid helped penicillins like ampicillin and amoxicillin kill resistant strains of Staph, but it didn’t work as well against other pathogens.

It turned out it had a hard time penetrating the cell. But it wasn’t entirely a failure, because olivanic acid was built on carbapenem, and this became the basis for two big medicines. The first of these was clavulanic acid, an even more effective beta-lactamase inhibitor than olivanic acid.

And while it wasn’t effective against all the penicillinases out there, scientists have found better combinations of beta-lactams and beta-lactamase inhibitors since then. Like amoxicillin pairs well with clavulanic acid, to become a product known as Augmentin. The other carbapenem worth noting though is thienamycin. It’s a broad spectrum antibacterial that also inhibits beta-lactamase.

It was actually first reported as a natural antibiotic in 1976, but scientists couldn’t make it in high quantities. Luckily, the synthetic version could be scaled up, which made it a useful antibacterial after all. Since thienamycin was tricky to work with, scientists tweaked it into imipenem and released it to market in 1985.

Carbapenem drugs are still mostly used as a last resort. Unfortunately, Enterobacteriacae developed enzymes against them too. And eventually the genes for those enzymes showed up on plasmids, which meant carbapenem resistance was about to get even worse. And this is where we switch gears.

Because while all of this is happening on the human side, there’s a whole other story playing out in agriculture. First thing’s first: Americans eat a lot of chicken. Like by multiple metrics, it’s our most popular animal protein. But this is a pretty recent change.

Because up until the 19 teens, most farmers would’ve had some chickens around, but mostly for eggs. Beef and pork were way more popular. Then around World War 2, Americans started demanding more protein, and farmers started breeding chickens to be much meatier.

There was even a contest called The Chicken of Tomorrow that offered prizes to whoever bred the most perfect chicken. So after world war 2, chicken production in the US shot up compared to before the war. And around this time, the scientific community was learning more about the importance of

Vitamins for preventing disease, both in humans and animals. The pharmaceutical company Merck found that Vitamin B12 was going to be an especially big deal in preventing livestock diseases. So scientists started looking for cheap sources of B12. One of those scientists was Thomas Jukes.

He was a nutrition scientist at Lederle Labs, The company that created aureomycin, the first commercially available tetracycline drug. Jukes knew that you could get B12, or what they called animal protein factor, from liver extract, but he wanted to find a cheaper alternative.

He also knew that the microbe that produced the antibiotic streptomycin also produced B12, so he and his colleagues designed an experiment. They gathered a small group of hens and roosters and fed them a low nutrient diet so that their chicks would be sick and scrawny.

Their eggs were hatched in an incubator, then separated into groups. The control group got the same low nutrient diet shown in Table 1 here, while experimental groups got the same diet, plus some kind of supplement that might improve their growth.

Some got a bunch of liver extract, some got synthetic B12, and some got a byproduct that was leftover from the tetracycline production process. It was a little more precise than that, but it was basically leftover Aureomycin swill. Then, each chick was weighed multiple times over the next 25 days, which coincidentally,

Started on December 1st and ended on Christmas day, 1948. In the end, very few of the chicks in the control group survived, and they were all low weight. But almost all the chicks in the experimental group lived; it was really just a matter of how big they got.

Interestingly though, they found a dose-response relationship in the aureomycin group. The higher the dose of antibiotic mash, the more the chicks weighed at 25 days. And unexpectedly, these chicks grew faster than the ones who got liver extract. So if you’re the scientist doing this experiment, you’d probably think that the antibiotic

Was the key factor that promoted growth, but Jukes had a really small sample size, so he and his colleagues weren’t so sure. They concluded the ‘“animal protein factor” was B12 plus some factor as yet to be identified’. In later experiments, Jukes added a mixture of powdered Aureomycin to the feed and the

Chicks gained even more weight. Unfortunately, he was running out of material for future trials; the existing Aureomycin was pretty much all being used for humans. But he managed to scrounge together some samples and sent them to agricultural scientists around

The country, who tested the drug in their own labs and confirmed, yep, something about aureomycin makes animals grow. And soon after that, researchers were showing that adding small doses of Aureomycin could speed up the growth rate of turkey chicks and pigs too.

But once word got from the scientific community to the agricultural community, demand for Aureomycin skyrocketed. Now all this time, this miracle, growth-promoting mash was in a murky middle ground of product. It wasn’t food, but it wasn’t a full scale medicine either.

And aureomycin for humans already had FDA approval, so what do you do from a legal perspective here? In September 1949 Jukes decided to file the patent for the mash as a supplement, a growth promoter. By 1950, nobody really knew how it worked, but they had the idea that it promoted growth

Better than regular old B vitamins. But we had seen antibiotic resistance in humans at this point, so a handful of staff at Lederle raised some red flags. Regardless, the FDA approved these new antibiotic formulations as growth promoters for animals in 1951. From there, the scope and promise of Aureomycin kept increasing in agriculture.

Lederle started marketing Aureomycin not just as a growth promoter but as a way to prevent disease in the first place. They got FDA approval for that purpose in April 1953. And then Lederle said, still not enough antibiotics. There’s room for more.

They started dipping the chicken meat in a diluted solution of Aureomycin before packaging it. And they called this process Acronization. Lederle’s parent company, Cyanamid, made millions of dollars off of it. Also, is it the taste of freshness? Or is it maybe the antibiotics you bathed in?

All of this is sounding a lot like the misuse in humans. Antibiotics were the hot new thing so we added them to everything. But at this point, it didn’t seem like it was leading to any health problems in humans, so no harm no foul, right? Well, not for long.

In the latter half of 1956, there was a big Staph outbreak across blue collar men in Seattle. At that point, epidemiologists knew that Staph could easily spread within a hospital, but unlike past epidemics, the victims of this outbreak seemed unrelated.

After a little investigation, it turned out that they all worked at the same poultry-processing plant, which had started acronizing their meat a few months earlier. The epidemiologist in the Seattle case, Reimert Ravenholt, started calling the farms where the raw chickens came from.

He interviewed farmers, and learned about Aureomycin being used all along the process. He reasoned, correctly, that the low doses of antibiotic used along the way had eliminated all but the most resistant bacteria. And by the time the meat got to the processing plant, the resistant bacteria were primed

To infect any exposed cut in the workers’ hands and arms. Ravenholt convinced the owners of the slaughterhouse to stop using acronization, and new infections stopped soon afterwards. It was a lot like the John Snow and Broad Street pump story.

In an October 1961 article in Public Health Reports, he writes “the findings of investigations of several outbreaks of food poisoning in the community in recent years suggested that considerable staphylococcal disease may derive from nonhuman reservoirs of infection”. This was a big deal.

We were learning that humans didn’t even need to consume the antibiotic to get infected with a resistant strain of the germ. After that, USDA scientists did experiments where they replicated the Acronization process and came to the same conclusion that Ravenholt did: resistant bacteria were leftover on Acronized meat, but not non-Acronized meat.

This started to turn public sentiment against Acronizization, and in 1966, the FDA said it was no longer okay to add antibiotics during packaging. Still nothing about adding antibiotics to the feed, but at least they were taking action. But there was still so much they didn’t know.

Like how could these germs spread from animals to humans? And how was it that bacteria could be resistant to more than one antibiotic? Well, in the late 1950s, a few Japanese researchers were studying multidrug resistant Shigella — the bacteria that causes dysentery.

What was weird about these cases was how these bacteria had developed resistance to drugs their host had never been exposed to. Like a patient could’ve been treated with tetracycline, but their Shigella was resistant to tetracycline and chloramphenicol and sulfonamide. They concluded that bacteria could share pieces of resistance genes with bacteria that hadn’t

Been exposed to the antibiotic yet. They called these pieces of genes R-factors. According to Tsutomu Watanabe, “R-factors are intracellular genetic elements of bacteria that transfer drug resistance makers to other bacteria by causing conjugation (or cell to cell contact). They can be transferred to other bacteria in the absence of transfer of host chromosomes,

Indicating that they are extrachromosomal or cytoplasmic elements”. That meant it was a separate pathway than regular old inheritance. If this sounds familiar, it’s because R-factors became the basis of our understanding of plasmids. So to recap, it’s the mid 1960s and we have evidence saying that usings antibiotic in

Agriculture selects for resistant bacteria, and those bacteria can infect humans. You would think that now would be the time for government intervention, right? Not quite. The British government had actually tried to investigate agricultural antibiotic use before. A committee run by a guy named James Turner published a report in 1962 and it concluded

That growth promoters were totally fine and posed no threat to human health. The problem was that James Turner was the president of the National Farmers’ Union, and a high-up at a fertilizer company. So there was a little conflict of interest there.

Fast forward to 1969 though, and a new British research committee arrived at a different conclusion. “There is ample proof that the giving of antibiotics to animals encourages the emergence of resistant strains of microorganisms. Equally, there is no doubt that many micro-organisms, whether resistant to antibiotics or not, whether

Potentially harmful to man or not, can be transmitted from animals to man in a variety of ways. Hence, where man and animal share a common microbial pathogen, there can in many cases be no doubt that the giving of antibiotics to animals encourages the prevalence of resistant pathogenic micro-organisms in man”.

This document became known as the Swann Report. The authors recommended that if an antibiotic could be used to treat disease, then it shouldn’t be given to animals as growth promoters. They recognized that antibiotics were still appropriate for treating disease, but growth promoters needed be treated differently.

The UK government listened and banned agricultural growth promoters in 1971. Meanwhile the United States did not. After the Swann Report, the FDA assembled a similar committee, which talked to the FDA in 1972 and recommended a similar ban. But obviously the Agricultural and Pharma industries didn’t like this and pushed back

Against any FDA action. The FDA caved and proposed a compromise: if you wanted to keep selling an antibiotic as a growth promoter, you’d need to prove its safety, otherwise it would be banned after 1975. But then in 1977 the FDA got a new commissioner; a guy named Donald Kennedy, and he came in

Hot. Within a few weeks of taking the job he proposed a ban of growth promoters in agriculture. Of course, this got a lot of pushback too. It’s kind of like what we saw with the tobacco companies in the smoking video.

The side that represented industry said “Yeah but can we really say that it’s cause and effect? We don’t think the science is settled”. In the end, politics got in the way and the ban wasn’t passed. But these days, we have even more evidence showing that feeding antibiotics to animals contributes to antibiotic resistance.

And evidence showing that these pathogens can be spread to humans. Knowing this, the European Union banned growth promoters in 2006, while the United States tiptoed around regulation a little bit more. The FDA did set up a resistance monitoring program in 2006 with the USDA and CDC, and

In 2005 they banned fluoroquinolones in chicken. But we never got our version of a Swann Report. So now it’s the 2000s, and we’ve got a problem. The antibiotics that used to be considered miracle drugs are no longer miracles. In the twenty teens, a bunch of high profile organizations said “alright, this is enough

And we need to do something about it”. So rapid fire here: In 2013, the CDC released a big report. In 2015, President Obama told the National Security Council to do something about antibiotic resistance. In 2016 a UN General Assembly of 70 governments declared it a global crisis.

The World Health Organization, G7 and G20 followed suit. In 2013, the FDA finally published Guidance For Industry number 213. GFIs aren’t law or bans; they’re more like formal write ups of what the FDA thinks about a topic. GFI 213 asked pharmaceutical companies to voluntarily remove growth promoting from their antibiotic labeling.

It also said that farmers would need a prescription from a veterinarians to use antibiotics in certain other ways. The goal was to reduce unnecessary antibiotics from agriculture by 2017. Now, on one hand, I’m glad that the US finally implemented something, but it does kind of

Deflate the Chik Fil A story I opened the video with. Like, farms were transitioning off of growth promoters by 2017 anyway. It’s not that fast food companies removed antibiotics out of a genuine concern for public health, but because the government was steering the industry that way anyway.

To give them credit though, Chik Fil A, Chipotle, and Panera went above and beyond the base requirements. So kudos. But clearly, resistance is still a big problem. Today, antibiotic resistant germs are directly responsible for over a million deaths around the world and contribute to 5 million deaths.

And of course, it’s way worse in low income countries. But wealthy countries are still at risk too — resistant germs kill over 35 thousand Americans a year. The worrying thing is that antibiotic discovery has slowed down massively since the golden age of antibiotics.

At the peak, we had 155 FDA approved antibacterial compounds, but now there’s only between 90 and 100. There have been new antibacterials though. Like the oxazolidinones which interrupt RNA translation, and the cyclic lipopeptides like daptomycin which basically poke holes in the cell membrane.

There are some other last-resort antimicrobials too, like Colistin and polymyxin B which are still useful, but they come with some heavy side effects like potential toxicity. Unfortunately, we mostly keep finding antibiotic compounds with same mechanisms that bacteria had already developed resistance too. So we need to find more treatment options.

But that’s going to involve some big shifts in how we fund and incentivize antibiotic research. One of the biggest technical hurdles is finding a good source of antibiotics. Historically, the way most scientists found antibiotics was by putting a microbe on a

Petri dish full of bacteria, then seeing which microbes kept the microbes from growing. The problem is that very few microbes actually grow in traditional petri dishes with agar. So if you want to identify a new antibiotic with the old school method, you’re limiting yourself to a super small slice of the microbial milieu.

So in the early 2000s, microbiologists realized that if they could come up with a method for culturing bacteria that didn’t use a Petri dish, they could identify more bacteria, which might mean unlocking entirely new antibiotic platforms. A solution came in 2010 with the isolation chip, or iChip, which is not an Apple product.

This thing is a device with a super fine grid that isolates individual cells in each channel. The original authors of the research paper found that they could culture entirely different kinds of bacteria than could be cultured on a petri dish.

In 2015, a group of American and German researchers published a paper in the journal Nature describing a new antibiotic they’d discovered using this method. One of their best candidates came from a bacteria they named Eleftheria terrae, a soil bacteria that produced an antibiotic they called Teixobactin.

They found that it was really good at killing Gram positive bacteria, including Staph, C diff, and even anthrax, but it was less effective Gram negative bacteria. The authors could tell that Teixobactin kept the cell from making peptidoglycan, that important part of the cell wall, but they weren’t totally clear how it worked.

Unlike beta-lactams, which bind to the enzyme that ties peptidoglycan together, teixobactin was probably messing with a precursor to peptidoglycan. Those same researchers tested it in mice infected with MRSA and others with Streptococcus pneumoniae — teixobactin worked even better than Vancomycin.

As a huge bonus, the researchers were also confident that pathogens would develop resistance to teixobactin more slowly than other antibiotics. Now, as of the time of writing, teixobactin is still in preclinical trials, but according to NovoBiotic’s press page, the company producing it, they’re at least getting some funding for it.

Another strategy for finding candidates is with Whole Genome Sequencing. Now I’m definitely not an expert on this, but as I understand it, sequencing a germ’s genome lets scientists predict what kind of proteins the germ will make, and what kind of resistance mechanisms it might have.

And that gives them more information about what kind of antibiotics might work against them. Finally, as a resident of Silicon Valley, I’m obligated to mention artificial intelligence. Remember that the earliest approaches to finding antibiotics were labor intensive numbers games. Test a bunch of microbes and hopefully you got lucky.

AI is really good at doing that grunt work. So if scientists already have whole genome data, AI could be used to predict resistance patterns that we didn’t already know. But all of these medical breakthroughs can’t happen without money. Because at the end of the day, developing antibiotics is a terrible business move.

When deciding whether or not to develop a drug, pharma companies try to estimate how much profit they’ll make and how much it’ll cost to develop. Cancer treatments, heart, and skin treatments are way more likely to make back those development costs, while antibiotics are not.

On average it takes over 10 years and a billion dollars to discover and develop a novel antibiotic. Plus, there’s a high failure rate. Only about 10% of antibiotic candidates move from preclinical testing to testing in humans. That number is closer to 65% for some cancer treatments.

So you can pour millions of dollars into R&D before your new antibiotic even gets into a human. From there, it’s just a matter of time before bacteria develop resistance to your new medicine, so even in the best case scenario, your money-making potential is inherently limited.

And in the long run, antibiotic production is a terrible financial strategy. Furthermore, they’re a product meant to be used for a short amount of time, in small quantities, and with the goal of never needing to use them. Doctors know their supply of effective antibiotics is shrinking, so they may try to hold off

On prescribing a brand new antibiotic until all the other options have been used. This is why the majority of big pharmaceutical companies don’t research antibiotics anymore. One Lipitor is more valuable than a dozen antibiotics — maybe a hundred. Instead, most antibiotic research happens in academia and small companies.

Unfortunately all those R&D costs represent a larger chunk of their funding, which makes it a riskier move for them. So the question becomes: how do we financially incentivize pharma companies to research antibiotics? Well high level, there are push incentives and pull incentives.

Pushes support research and development while pulls reward firms who successfully bring a product to market One idea is an Options market. Basically, investors act like crowdfunders. They help fund development of a new antibiotic, then if the drug comes out, they can sell the drugs to hospitals.

Free market folks love this, but it disadvantages low income countries since investors can easily price gouge. The FDA is also considering a subscription based system. Hospitals and governments would need to pay a subscription, which goes towards pharma R&D, then the healthcare providers can access the antibiotics once they’re developed.

Another option is government awards. Basically, as soon as a company develops a new antibiotic, the government pays them a lump sum of money. That way, they immediately recoup some of their costs, instead of waiting for years. That also helps minimize the risk of losing money due to resistance.

For example, the FDA Safety and Innovation Act of 2012 offered a faster approval process and a longer exclusivity period if they could make certain drugs. Next, there are biotech accelerators that work kind of like venture-backed startups. The best example I could find was CARB-X based out of Boston University.

They’re a lot like a tech startup accelerator, but instead of Airbnbs, they churn out antimicrobials. And instead of Mark Cubans, they’re funded by governments and non-profits. There are a few other economic ideas, but there’s also the obvious strategy — prevention.

Since animal health got us into this mess, public health experts advocate for something called the One Health approach. One Health goes beyond antimicrobial resistance and basically says, if we keep animals healthy, we’ll lessen the burden of human disease. There is one more strategy that scientists are excited about.

It uses specific viruses called bacteriophages to target bacterial infections. But that story involves a renegade microbiologist, Soviet science, and the desperate rediscovery of a lifesaving therapy. It was such a good story, I had to make a full video about it.

So in the next and final episode of the antibiotic series, we’ll hear the story of phage therapy.