The problem of antimicrobial resistance

Introduction

Welcome to The problem of antimicrobial resistance, an introductory module aimed at all learners. Many basic concepts are introduced in this module and will be discussed in more detail in other modules.

The problem of antimicrobial resistance will take you back in time to gain insight into our understanding of prevention and treatment of infectious diseases. You will learn about hygiene theory, germ theory and the discovery of antibiotics. You will gain an understanding of the importance of antibiotics in modern medicine and other aspects of modern life. Unfortunately, the antibiotics that we have today are becoming less effective in the treatment of infections due to antimicrobial resistance. This is a very big threat to global health. You will learn how resistance develops in bacteria and what the drivers are. In the final section you will learn about ongoing global efforts to tackle the problem of antimicrobial resistance (AMR), and finally reflect on what you can do to bring about change.

By the end of this module, you should be able to:

• define the term ‘antibiotic’ and describe the importance of antibiotics in modern society
• explain how the overuse and misuse of antibiotics contribute to bacterial resistance
• describe the scale and nature of antibiotic resistance worldwide, and discuss the consequences of a future without antibiotics
• explain why the problem of AMR needs a One Health approach
• reflect on your own role and those of your colleagues in tackling the AMR crisis.

1 Life before antibiotics

The problem of antimicrobial resistance (AMR) is a universal issue that we could all be directly or indirectly impacted by. AMR was responsible for an estimated 700,000 deaths worldwide in 2016; if we don’t act now, this number is likely to increase in the future.

This section provides an historic perspective on important developments that have shaped modern medicine and provides insights to understanding the problem of AMR that we face today.

After completing this section you will:

• understand how concepts related to the prevention, causes and treatment of infectious diseases developed over time
• understand the importance of good hygiene measures in preventing infections
• understand the importance of antibiotics in modern medicine and modern life
• appreciate that the pre-antibiotic era is not that long ago.

1.1 Medicine in the 1800s

In order to better understand some key aspects of modern medicine, we first go back to a time when we did not know much about infectious diseases; a time when an infection that can now be easily treated and cured could kill you.

Activity 2: Living and dying in the 18th century

Watch Video 1, about the death of George Washington in 1799. As you watch, keep the following questions in mind:

• What did doctors think caused the disease?
• What treatment was given to George Washington?
• What might have caused this disease?
• What kind of treatments are available today?

Download this video clip.Video player: Video 1

Show transcript|Hide transcript

Transcript: Video 1

MICHAEL MOSLEY:

On Saturday the 14th of December, 1799, George Washington, one of the founding fathers of the United States of America, lay dying. A couple of days earlier, he'd been out riding in cold and wet weather. He developed a sore throat. Early on the Saturday morning he said to his wife, I'm feeling very ill.

Within hours, his personal physicians had arrived, the finest in the country, the best money could buy. They had all sorts of suggestions as to what was making him ill – his humours were unbalanced, or perhaps he breathed in miasmas, foul air. His doctors gave him the standard medical treatment for someone who was as severely ill as he obviously was.

They took a knife, found a vein, and bled him – repeatedly. They drained him of more than four pints of blood. By nightfall, Washington was fading fast, so his physicians applied even more ‘scientific’ treatments. This Spanish fly, although it's actually a green beetle. They would have ground it up and then applied the paste to his throat. But all that did was blister the skin.

He said to his doctors, I die hard, but I'm not afraid to go. By late that evening, the first president of the United States was dead. Washington probably died from a simple infection. At the end of the 18th century, it made no difference if you were a pauper or the president. What you got was little more than quackery.

The Centers for Disease Control and Prevention in Atlanta is not for those of a nervous disposition. It holds some of the world's most deadly life forms. This facility contains some of the greatest evils ever collected in one place. This bacteria causes the plague. Your flesh dies and rots while you're still alive.

The Black Death of the 14th century killed a quarter of Europe's population. And then there's tuberculosis, a slow and deadly killer, the creator of oozing lung abscesses. The poet Keats, all three Brontë sisters, and Chopin are a few of its more artistic victims. And this is gangrene caused by any number of bacterial infections that lurk unseen in every dirty bullet, scalpel and delivery ward.

Some bacteria don't need a wound to get inside you. They're already there, waiting patiently. Patiently for our defences to drop, and then they pounce. That's probably what did poor George Washington.

DR DRUIN BURCH:

In 1790s America, sudden death was utterly common. And you clustered round people's bedside when they got cold and when they got chills because they could die.

MICHAEL MOSLEY:

Washington's doctors would have laughed in your face if you'd told them that microscopic life was killing him. They still clung to theories passed down from the ancient Greeks.

DR WALTER SNEADER:

They believed that if you had a disease, the humours were out of balance. If you had a fever, you were considered to have an excess of a blood humour– well, you were flushed after all.

End transcript: Video 1

Download

Video 1

Interactive feature not available in single page view (see it in standard view).

Answer

• What did doctors think caused the disease?
  • His humours were unbalanced, or perhaps he breathed in miasma (foul air).
• What treatment was given to George Washington?
  • They drained his blood (blood-letting).
  • They applied ground-up green beetle on his throat.
• What do we now know about what might have caused this disease?
  • Microscopic organisms can cause infectious diseases, such as the one that attacked George Washington’s throat. Other examples of diseases caused by microbes are bubonic plague, tuberculosis and gangrene.
• What kind of treatments are available today for management of infections caused by microbes?
  • We now know that infections are caused by microscopic organisms (microbes), including bacteria. Antibiotics are used to treat infections caused by bacteria. (You will learn more about antibiotics in the next section.)

1.2 Discoveries in modern medicine

A lot has changed since the 1800s: our understanding of the causes, treatment and prevention of infectious diseases has considerably improved. In this section you will learn how our knowledge developed, who contributed to developing new insights and why this new approach was so revolutionary at the time.

Activity 3: Development of hygiene theory

Watch Video 2 on the discoveries of Ignaz Semmelweis, a physician working in Vienna in the mid-19th century, and answer the question that follows.

Show transcript|Hide transcript

Transcript: Video 2

Years before the germ theory of disease was developed, the Viennese physician Ignaz Semmelweis came to the startling discovery that doctors could save the lives of patients simply by washing their hands. Although he couldn’t explain why hand disinfection was so effective, his research in 1847 would go on to transform the way surgery is carried out and infectious diseases are controlled today.

Known locally as the saviour of women, Semmelweis initiated handwashing policies which helped to drastically reduce the mortality rate from childbed fever in Viennese obstetrics clinics where he worked.

Childbed fever, or puerperal fever, is the infection of the female reproductive organs following childbirth and was a common cause of death at the time. Semmelweis’ attention was first drawn to the mortality rates at the clinics he worked at, because women would beg to be admitted to the clinics run by midwives rather than those staffed by students. The women were so desperate to avoid the student clinics that they would rather give birth in the street. After looking into the mortality rates of the two clinics, he found that the student run clinic did indeed have a much higher mortality rate for puerperal fever – sometimes three times higher. After eliminating various factors, Semmelweis came to the conclusion that the students carried something from the dissection rooms where they performed autopsies, to the patients they examined during labor. He ordered the students to wash their hands in a solution of chlorinated lime before each examination. The mortality rate fell from 18 per cent to 1 per cent.

Despite the success of this policy, Semmelweis faced the wrath of the medical community. He could offer no acceptable explanation for his findings as the notion that there were germs causing disease was unaccepted, and various doctors were offended by the insinuation that their hands were dirty. He was ostracised and ridiculed by the leading medical figures of his time, and eventually driven out of Vienna.

After struggling for years to promote his hand disinfection policies, Semmelweis was admitted to an insane asylum at the age of 47. He died 14 days later.

End transcript: Video 2

Video 2

Interactive feature not available in single page view (see it in standard view).

What did Ignaz Semmelweis discover?

Answer

He discovered that doctors could save lives by simply washing their hands.

Semmelweis was not the first person to see the connection between hygiene and the spread of puerperal fever (childbirth fever); Alexander Gordon had made a similar observation about 50 years earlier. He discovered that puerperal fever was spread from patient to patient by the attending midwife or doctor. To limit the spread of the disease, he recommended fumigating clothing and burning bedlinen used by women with puerperal fever. He also recommended the cleanliness of the attending doctors and midwives.

At the time that Gordon and later Semmelweis made their discoveries on the importance of hygiene in the spread of disease, they did not know what actually caused infections. That discovery was made a few years later by the collective efforts of Louis Pasteur and Robert Koch, whose discovered that diseases were caused by microscopic organisms – which they called ‘germs’.

Discovery of antibiotics

After germ theory was established, people knew what caused infectious diseases. The search for a cure for these diseases had begun.

In 1928, Alexander Fleming discovered which penicillin killed bacteria. Florey and Chain played an important role in making penicillin widely available.

Download this video clip.Video player: Video 3

Show transcript|Hide transcript

Transcript: Video 3

NARRATOR:

Microbes, mostly tiny bacteria, make up around 90% of the cells in a typical human body and 10% of our body weight. Most of them are in our gut and on our skin. Many microbes are beneficial, for example, helping us to digest our food. Only a tiny fraction cause disease, and are usually kept in check by our immune system. But when they aren't, microbes also help us to fight back.

Bacteria cause disease when they are able to reproduce in the body. They produce harmful substances called toxins, which damage tissues and organs. But in nature, microbes can also produce agents called antibiotics to protect themselves against competitors.

PROFESSOR CHARLES COCKELL:

It's a tough world out there. And you might think that you just see competition in the savannas of Africa. But in fact, the microbes fight each other as well. And in fact, like martial arts, they have ways of fighting other microbes with particular moves. And one move they have is to produce antibiotics. These are compounds that allow them to kill other microbes and take all the food for themselves, all the resources that they need. And so the competition between microbes results in these very sophisticated antibiotic molecules.

NARRATOR:

The discovery of antibiotics and their power to fight bacterial disease began with Alexander Fleming. He observed the mould Penicillium notatum accidentally growing on a sample of staphylococci, and saw it had killed the surrounding colonies of disease causing bacteria.

DR PAULA SALDAGO:

All antibiotics work by disrupting a critical function in the bacterial cell. For example, penicillin, discovered in 1928, prevents the cell from renewing its cell wall during growth. Eventually, the cell wall weakens and bursts.

NARRATOR:

By the 1950s, the use of antibiotics had revolutionised the treatment of previously untreatable infectious diseases. In 1967, the Surgeon General of the United States of America, William Stewart, declared, ‘The time has come to close the book on infectious diseases. We have basically wiped out infection in the United States’. But Stewart's optimism proved premature.

PROFESSOR CHARLES COCKELL:

The bad news is that microbes can become resistant to antibiotics, and they can change their biochemistry in order to adapt to these antibiotics and prevent the antibiotics from damaging the cell.

NARRATOR:

It's standard evolutionary behaviour. When bacteria reproduce, chance mutations occur. Most will be useless. But sometimes there will be one that will protect the bacterium against a particular antibiotic. While most of the bacteria succumb to the antibiotic, the one that survives goes on to reproduce and replicate the resistance. And bacteria reproduce very fast.

DR PAULA SALDAGO:

The good news is that scientists are developing new synthetic antibiotics that target resistant bacteria.

NARRATOR:

But who knows whether one day a mutated bacterium might become resistant to all synthetic antibiotics, a super, super bug.

[MUSIC PLAYING]

End transcript: Video 3

Download

Video 3

Interactive feature not available in single page view (see it in standard view).

In Section 2.2 you will learn more about what antibiotics are, and in Section 2.3 you will learn more about what antibiotics do.

2 The golden age of medicine

In this section you will learn about antibiotics: what they are, how they work and the important role they play in modern medicine but also modern life. Here, you will be introduced to the basic concepts that will be explained in more detail in other modules in this course.

After this section you will be able to:

• define the term ‘antibiotic’ and give examples
• describe how antibiotics work
• describe the role of antibiotics in modern medicine and modern life.

2.1 What bacteria are

Figure 1 Bacteria: they get everywhere!

Show description|Hide description

A cartoon of a bacterium holding a sign that it is all over the place

Figure 1 Bacteria: they get everywhere!

Bacteria are the most numerous organisms living on Earth. They live all around us: in our gut, in the soil and in water. Bacteria are pretty much all over the place.

Activity 5: Bacterial growth

The secret of the success of bacteria – why there are so many of them – is that they can reproduce rapidly. Under the right conditions, some types of bacteria can replicate every 20 minutes. Take a look at Video 4 to see what this looks like, and answer the question that follows.

Download this video clip.Video player: Video 4

Show transcript|Hide transcript

Transcript: Video 4

NARRATOR:

These rod-shaped bacteria are about to replicate. There are eight in this culture, but each bacterial cell is about to divide into two. Now there are 16 bacteria, and soon there will be 32.

Under ideal conditions, some bacteria can divide in as little as 20 minutes. A bacterial infection can take hold so quickly because bacteria can double their numbers in such a short time unless something keeps them in check. Handwashing with soap, vaccination to boost the immune system, and anti-bacterial drugs may halt this replication cycle. But left unchecked, in less than four days, this bacterial culture would weigh as much as the Earth.

End transcript: Video 4

Download

Video 4

Interactive feature not available in single page view (see it in standard view).

The video mentions that a bacterial infection can take hold so quickly because bacteria can double their numbers in such a short time. What are the three options mentioned in the video that help to stop the growth and replication cycle of bacteria?

Answer

The three options are:

• handwashing with soap
• vaccination to boost the immune system
• antibacterial drugs.

Most bacteria do not cause us any harm. However, a small group of bacteria – about 500 species – can cause diseases in humans, animals and/or plants. These bacteria are called pathogenic, and they are capable of causing an infection by evading the host’s normal defences and invading cells or tissues. They may also produce harmful toxins (poisons).

Many bacteria are opportunistic pathogens, meaning that they can cause an infection when the defence mechanisms of the host – which could be a human, animal or plant – are weakened.

2.2 What are antibiotics?

Activity 7: What are antibiotics?

Watch Video 5, on antibiotics:

Download this video clip.Video player: Video 5

Show transcript|Hide transcript

Transcript: Video 5

NARRATOR:

Microbes, mostly tiny bacteria, make up around 90% of the cells in a typical human body and 10% of our body weight. Most of them are in our gut and on our skin. Many microbes are beneficial, for example, helping us to digest our food. Only a tiny fraction cause disease, and are usually kept in check by our immune system. But when they aren't, microbes also help us to fight back.

Bacteria cause disease when they are able to reproduce in the body. They produce harmful substances called toxins, which damage tissues and organs. But in nature, microbes can also produce agents called antibiotics to protect themselves against competitors.

PROFESSOR CHARLES COCKELL:

It's a tough world out there. And you might think that you just see competition in the savannas of Africa. But in fact, the microbes fight each other as well. And in fact, like martial arts, they have ways of fighting other microbes with particular moves. And one move they have is to produce antibiotics. These are compounds that allow them to kill other microbes and take all the food for themselves, all the resources that they need. And so the competition between microbes results in these very sophisticated antibiotic molecules.

End transcript: Video 5

Download

Video 5

Interactive feature not available in single page view (see it in standard view).

Now write down in your own words a definition of antibiotics.

Discussion

Compounds that are made by microbes to fight other microbes are naturally occurring antibiotics. Scientists have copied and often modified these compounds to use to fight bacteria in humans, animals and plants.

2.3 What antibiotics do

Antibiotics that are used for medical treatment work through a mechanism of selective toxicity: they attack the bacteria that cause the infection but they don’t kill the patient. They often also attack bacteria that are not pathogenic.

That seems very obvious now, but let’s briefly go back in time again. Not even that long ago – let’s say about 100 years …

At that time there was some understanding about the importance of hygiene measures to prevent spread of infectious disease. However, infections were difficult to treat, because the treatments that were available not only killed the infection, but also often killed the patient.

The discovery of antibiotics was the discovery of ‘magic bullets’: a treatment was now available that only targeted microbes and therefore kept the patient alive.

Not all antibiotics attack bacteria in the same way: some attack the cell wall, some attack bacterial protein syntheses and some attack the DNA-replicating mechanism of bacteria. In all cases, they tackle structures or biochemical processes that are either not found in human or animal cells, or don’t work in the same way. Antibiotics are classified based on their chemical structure: those with a similar chemical structure tend to have similar antibacterial activity. (You will learn more about this in Introducing antimicrobial resistance.)

Some classes of antibiotics target several bacterial species: these are called broad-spectrum antibiotics. Antibiotics with a working mechanism that only attacks a small group of bacterial species are called narrow-spectrum antibiotics.

2.4 Role of antibiotics in modern medicine

In the previous sections you learned that:

• pathogenic bacteria can cause infection in humans, animals and plants
• antibiotics are used to treat bacterial infections.

However, antibiotics can be used in other scenarios, beyond the treatment of infectious diseases.

2.5 The role of antibiotics in food production

In the previous sections you learned that:

• pathogenic bacteria can cause infection in humans, animals and plants
• antibiotics are used to treat bacterial infections
• antibiotics are also used to prevent infections in patients with weakened immune systems, for example in cancer patients

3 The problem of antibiotic resistance

In this section you will learn about antibiotic resistance and reflect on its implications for modern medicine and other aspects of our lives. In the previous section you learned about the importance of antibiotics today. In this section you will reflect on what a future without effective antibiotics would look like. You will also study figures and maps to get an understanding of the global scale of the problem of antibiotic resistance.

After this section you will:

• be able to define the term antibiotic resistance
• understand the scale of the problem of antibiotic resistance
• be able to reflect on a future without functional antibiotics.

3.1 Definition of resistance

Activity 13: Understanding resistance

Watch the following video on antibiotic resistance, up to 2:38. Don’t worry if you hear some terms in this video that you are unfamiliar with; it is important that you understand the overall concept of resistance to antibiotics in bacteria.

Show transcript|Hide transcript

Transcript: Video 6

[MUSIC PLAYING]

NARRATOR:

What if I told you there were trillions of tiny bacteria all around you? It's true. micro-organisms called bacteria were some of the first life forms to appear on Earth. Though they consist of only a single cell, their total biomass is greater than that of all plants and animals combined. And they live virtually everywhere, on the ground, in the water, on your kitchen table, on your skin, even inside you.

Don't reach for the panic button just yet. Although you have 10 times more bacterial cells inside you than your body has human cells, many of these bacteria are harmless or even beneficial, helping digestion and immunity. But there are a few bad apples that can cause harmful infections, from minor inconveniences to deadly epidemics.

Fortunately, there are amazing medicines designed to fight bacterial infections. Synthesised from chemicals or occurring naturally in things like mould, these antibiotics kill or neutralise bacteria by interrupting cell wall synthesis, or interfering with vital processes, like protein synthesis, all while leaving human cells unharmed.

The deployment of antibiotics over the course of the 20th century has rendered many previously dangerous diseases easily treatable. But today, more and more of our antibiotics are becoming less effective. Did something go wrong to make them stop working? The problem is not with the antibiotics, but the bacteria they were made to fight. And the reason lies in Darwin's theory of natural selection.

Just like any other organisms, individual bacteria can undergo random mutations. Many of these mutations are harmful or useless. But every now and then, one comes along that gives its organism an edge in survival. And for a bacterium, a mutation making it resistant to a certain antibiotic gives quite the edge.

As the non-resistant bacteria are killed off, which happens especially quickly in antibiotic-rich environments, like hospitals, there is more room and resources for the resistant ones to thrive, passing along only the mutated genes that help them do so.

Reproduction isn't the only way to do this. Some can release their DNA upon death to be picked up by other bacteria while others use a method called conjugation, connecting through pili to share their genes. Over time, the resistant genes proliferate, creating entire strains of resistant super-bacteria.

End transcript: Video 6

Video 6

Interactive feature not available in single page view (see it in standard view).

In your own words, what is antibiotic resistance?

Discussion

Bacteria have developed ways to defend themselves against the antibiotics that other microbes produce. When bacteria can withstand attack by the antibiotic, they are termed resistant to that antibiotic.

Bacteria can be innately resistant or acquire resistance. (You will learn more about this in the module Introducing antimicrobial resistance.) The first, innate resistance, is a natural state of some bacteria. For example, some organisms may have innate resistance because the antimicrobial cannot pass the bacterial cell wall. Examples of innate resistance include Enterococci, which can withstand the effects of cephalosporins, and Klebsiella species that are not susceptible to penicillin V.

Resistance can also be acquired. The two major ways of developing acquired resistance are through genetic mutation or through gene transfer. Bacteria mutate with a high frequency: not all of these mutations lead to antimicrobial resistance, but some do. Even the slightest selective advantage brought about by a mutation can result in an organism out-competing its neighbours. Bacteria with a resistance gene can transfer it to another bacterium, which then acquires resistance (gene transfer).

Remember: bacteria are the ones that get resistant to antibiotics – not people, animals or plants.

The term ‘antimicrobial resistance (AMR) is used to describe this phenomenon. Although it technically includes resistance to all microbes, in this course it will generally be used to refer to antibacterial resistance.

In Section 4 we will look at the development and drivers of resistance in more detail, but first let’s take a moment to think about what this means for modern medicine (human and veterinary), and agriculture at the global scale.

3.2 Consequences of resistance

3.3 Scale of resistance

Although we would not go back to life as it was in the 19th century if we lost antibiotics, we should definitely not underestimate the impact that losing them would have on global health.

In 2016, the UN assembly gathered to discuss the problem of AMR and called it one of the biggest threats to global health. This was only the fourth time in the history of the UN that a health topic was discussed at its General Assembly – the other three were HIV, noncommunicable diseases and Ebola (WHO, 2016).

Activity 15: Resistance of Acinetobacter baumannii to carbapenems

Now let’s look at the scale of resistance worldwide.

Acinetobacter baumannii is an opportunistic pathogen that can cause a range of diseases, including pneumonia and bloodstream infections. Carbapenems are a class of highly effective broad-spectrum antibiotics, usually reserved for treating multi-drug-resistant infections. The fact that this species has developed resistance to such an effective and important antibiotic class is particularly worrying.

In Figure 2 you see the resistance that Acinetobacter baumannii has developed against a class of antibiotic known as carbapenems as documented by the Center for Disease Dynamics, Economics & Policy (CDDEP). The percentage of resistant isolates of Acinetobacter baumannii is indicated in blue; the darker the country, the higher the percentage of resistance. There are no data available on the countries in light grey.

Figure 2 Resistance of Acinetobacter baumannii to carbapenems.

Is data available from your country?

Which countries have the highest level of resistant isolates of Acinetobacter baumannii against carbapenems?

Discussion

The darker blue the country, the higher the proportion of isolates that were found to be resistant. High levels of resistance are found in Mexico, Venezuela, Argentina, South Africa, Tunisia, Poland, Ukraine, Spain, Italy, Greece, Turkey, Saudi Arabia, Russia, China, India and Pakistan.

Let’s zoom in to a few countries to see the percentage of Acinetobacter baumannii isolates found to be resistant over time. Take a minute to look at the trends of resistance in Russia, the United States and Venezuela (Figures 3–5).

The figures show the percentage of Acinetobacter baumannii isolates resistant to carbapenems over time in Russia, Venezuela and the United States in different years as documented by the CDDEP. Data are based on different data sources.

Different colours on the maps are assigned at random.

Figure 3 Antibiotic resistance of Acinetobacter baumannii in Russia. (Source: Central Asian and Eastern European Surveillance of Antimicrobial Resistance (CAESAR))

Figure 4 Antibiotic resistance of Acinetobacter baumannii in Venezuela. (Source: Venezuela: Programa Venezolano de Vigilancia de la Resistencia a los Antimicrobianos (PROVENRA))

Figure 5 Antibiotic resistance of Acinetobacter baumannii in the USA. (Source: United States: The Surveillance Network, USA/ResistanceMap Surveillance Network/National Healthcare Safety Network, USA)

What is the trend that you can identify on the percentage of Acinetobacter baumannii isolates resistant to carbapenems over time? What is different in the trend in the United States?

Discussion

In Russia and Venezuela, the level of resistance has increased over time. It is not increasing in a straight line, but the trend is going up. In the United States, the level of resistance increased until 2009 but started decreasing after that year.

Why are the timelines of the graphs different?

Discussion

The timelines of the graphs are different due to the practical reasons of the availability of information. In Section 5.3 you will learn about international efforts to standardise data collection on the levels of resistance of different pathogens all over the world.

Unfortunately, Acinetobacter baumannii is not the only type of bacterium that shows resistance to this class of antibiotics: several other types of bacteria have developed resistance to carbapenems or other broad-spectrum antibiotics such as cephalosporins and vancomycin. The WHO developed the priority pathogen list (see Table 1) for development of new antibiotics. This list (adapted from WHO, 2017) ranks antibiotic-resistant bacterial pathogens for which alternative treatments are urgently required, giving each a priority rating. As you can see, the priority rating for Acinetobacter baumannii is ‘critical’.

The WHO has also produced a list of priority pathogens for surveillance as part of its Global Antimicrobial Resistance Surveillance (GLASS) programme. This is a list of organisms in which high levels of resistance have been reported and are also some of the most common causes of bacterial infections. The priority pathogens for the GLASS surveillance (WHO, 2015) are:

• Acinetobacter baumannii
• Escherichia coli
• Klebsiella pneumoniae
• Neisseria gonorrhoeae
• Salmonella sp.
• Staphylococcus aureus
• Streptococcus pneumoniae.

As you may have noticed, there is a lot of overlap between the two lists.

4 How resistance develops

In the previous section you learned about the global scale and impact of AMR on modern life. In this section you will learn about the causes that contribute to this problem – specifically, the development and drivers of AMR.

After this section you will understand:

• that development of antibiotic resistance is a naturally occurring process that protects bacteria
• that increased use of antibiotics has sped up the natural process of resistance development
• how resistant bacteria spread in the environment
• that use of antimicrobials in different sectors is a driver for AMR.

4.1 Development of resistance

In Section 2.2 you learned that antibiotics occur naturally, although scientists have copied and modified those compounds to produce synthetic antibiotics, and most antibiotics in current use are not naturally produced. Just as the development of antibiotics is a naturally occurring process, so too is the development of resistance to antibiotics.

Activity 16: Antibiotic resistance occurs in nature

Watch this video about bacteria living very remotely from humans in a resource-scarce environment.

Download this video clip.Video player: Video 7

Show transcript|Hide transcript

Transcript: Video 7

MICHAEL MOSLEY:

It was in 2012, in a cave much deeper than I'm able to go, that Hazel's team made their breakthrough discovery.

HAZEL:

So the kind of areas that we sample look quite a bit like this.

MICHAEL MOSLEY:

Hazel took a bunch of bacterial samples from the cave and sent them off to a lab for analysis. The results shocked everyone.

HAZEL:

So I sent him just 100, and he started testing them. And he's like, you're not going to believe this, but they're resistant to everything. Everything that's used.

MICHAEL MOSLEY:

So these were bacteria you found on a wall in a cave.

HAZEL:

Much, much more remote than this, much further way.

MICHAEL MOSLEY:

That had not seen humans for ...

HAZEL:

We know humans had never been in there because we have the exploration records. So there was no impact on it. And they were resistant to practically every antibiotic that's used in the clinic.

MICHAEL MOSLEY:

That is both incredibly exciting and incredibly scary. Nobody had ever thought that you would find resistant bacteria down at the bottom of a bloody cave.

MICHAEL MOSLEY:

They’ve had no interaction with humans. But the bacteria Hazel found in the cave were resistant to a huge array of antibiotics we use in modern medicine. This resistance had clearly evolved over millions of years without us having anything to do with it. Why?

Well, it makes sense when you think of antibiotics not as man-made, but the byproduct of war between microbes. They make chemical weapons to destroy their enemies and steal their resources, weapons we have learned to exploit as antibiotics. The bacteria living deep in the cave have had millions of years to evolve weapons that can target and destroy even their toughest rivals. The battle for scarce resources, like nutrients and energy, is particularly brutal down here in the caves.

HAZEL:

It's really starved down here. There's no resources. It's probably one of the most starved environments on Earth. Because if you think about it, any energy needs to come in through the rock. And so there's a big competition for nutrients.

MICHAEL MOSLEY:

The fewer the resources, the more intensely the microbes battle. And that creates resistance. Because the bacteria under attack don't just lie back and die. When billions of bacterial cells are bombarded, all it takes is for one cell to mutate its DNA in such a way that the antibiotic can no longer kill it. This ability to resist then spreads fast. So developing resistance to antibiotics is an entirely natural process which the bacteria of Carlsbad have taken to the extreme.

End transcript: Video 7

Download

Video 7

Interactive feature not available in single page view (see it in standard view).

4.2 Spread of resistance in bacteria and the environment

Earlier in this module you learned that bacteria are all around us. Some types of bacteria are common to all living beings (humans, animals and plants). Remember from Section 2.1 how fast bacteria replicate?

Consider a few Salmonella bacteria that have infected a chicken. The chicken is treated with antibiotics, and one of the bacteria happens to be resistant to the antibiotic that is given. All the other bacteria will be killed by the antibiotic, but the resistant bacterium will survive, divide, multiply and pass the resistance to all offspring. In addition, bacteria can pass on resistance between each other by other mechanisms called horizontal transfer, which is explained in the module Introducing antibiotic resistance.

Activity 17: Spread of antibiotics in the environment

Study Figure 6 (from Berkner et al., 2014) on the different ways that antibiotics spread in the environment and answer the question that follows. Just as antibiotics can spread in the environment, so can some resistant bacteria.

Figure 6 The pathway of the spread of antibiotics in the environment.

Show description|Hide description

This figure shows the pathway of the spread of antibiotics in the environment. Starting with the application of antibiotic agents (red dots) in human and veterinary medicine in the upper left corner, the spreading of antibiotic residues in the ecosystem is drawn as a web of exposure pathways.

Figure 6 The pathway of the spread of antibiotics in the environment.

Identify three ways that antibiotics can end up in the groundwater.

Discussion

Three ways that antibiotics can end up in the groundwater are through:

• waste deposits from humans that contain antibiotic-resistant bacteria
• run-off from fields that have been fertilised with manure that carries antibiotic-resistant bacteria, or with sewage sludge from the sewage plant that carries antibiotic-resistant bacteria
• excrement or droppings from animals that carry antibiotic-resistant bacteria.

4.3 Drivers of resistance

Activity 18: Resistance to newly discovered antibiotics

Listen to part of a TED talk (between 3:49 and 5:00 in Video 8) and pay particular attention to the figure that appears onscreen at around 4:45, which summarises the development of resistance against different classes of antibiotics.

Show transcript|Hide transcript

Transcript: Video 8

Briefly, it works like this. Bacteria compete against each other, for resources, for food, by manufacturing lethal compounds that they direct against each other. Other bacteria to protect themselves, evolve defences against that chemical attack.

When we first made antibiotics, we took those compounds into the lab, and made our own versions of them. And bacteria responded to our attack, the way they always had.

Here is what happened next:

Penicillin was distributed in 1943, and widespread penicillin resistance arrived by 1945.

Vancomycin arrived in 1972; vancomycin resistance in 1988.

Imipenem in 1985 and resistance to it in 1998.

Daptomycin, one of the most recent drugs, in 2003, and resistance to it just a year later in 2004.

For 70 years, we played a game of leapfrog: our drug, and then resistance. And then another drug, and then resistance again.

End transcript: Video 8

Video 8

Interactive feature not available in single page view (see it in standard view).

The more antibiotics we use, the more we select for resistance. Any mutations (genetic changes) in bacterial genes happen by chance; if the genetic mutation leads to the bacteria becoming resistant to an antibiotic, and we continue to use the same molecule, the bacteria that do not have this resistance are killed, but the ones that carry the mutation survive. That is what we mean by ‘selecting for resistance’.

This process holds true for any newly discovered antibiotic. Evolution means that resistance will inevitably emerge, but it will do so more rapidly if we do not use antibiotics with care. Let’s look at some graphs on antimicrobial consumption (AMC) in the world.

Activity 19: Human antimicrobial consumption

Study Figure 7 and answer the questions that follow. It shows the percentage change in antibiotic consumption per capita between 2000 and 2010. Percentage decrease is indicated in blue while percentage increase is indicated in red. Lower percentage changes are indicated by lighter colours. No data are available for the countries shown in grey.

Figure 7 Country-specific human antibiotic consumption data, 2000–2010.

1. Is human antibiotic consumption data available for the country that you live in?
2. What global trend(s) can you identify in human antibiotic consumption?

Discussion

In some countries the consumption of antibiotics by humans has decreased between 2000 and 2010, and in others it has increased. Decrease of antibiotic consumption is seen in the Americas, most countries in Europe and in eastern Asian countries. Increase in antibiotic consumption is seen in South America, Africa and Asia.

Generally, based on Figure 7, you can say that in high-income countries the antibiotic consumption by humans has decreased between 2000 and 2010, whereas it has increased in low- and middle-income countries. However, no information is provided on the use of antibiotics, such as who they were given to and whether they were used appropriately. Understanding how antibiotics are used is another important factor in understanding the drivers of AMR.

Antibiotics are also used to keep animals healthy. This includes both companion animals and food-producing animals. Use of antimicrobials in companion animals is likely to have less impact on AMR than antimicrobial use in food-producing animals. Companion animal medicine is usually based on therapeutic treatment of a small number of individual animals, whereas antimicrobial use in food-producing animals sometimes occurs at a larger scale and may include use for prophylaxis or growth promotion. In addition, treatment of food-producing animals may result in resistant bacteria entering the food chain.

The Food and Agriculture Organization (FAO) states that estimates of the total use of antimicrobials in agriculture vary considerably. This is mainly due to a lack of systems in place to collect information on use of antimicrobials in animals, although in Section 5.3 you will learn that global efforts are being made to address this data gap. Antimicrobial use in livestock and in other food-producing animals such as aquatic animals is projected to increase over the coming decades based on the increased demand for animal-sourced food products (FAO).

Activity 20: AMR in aquaculture

Watch Video 9 (up to 0:50), which looks at AMR in aquaculture:

Show transcript|Hide transcript

Transcript: Video 9

Why antimicrobial resistance (AMR) in aquaculture matters for the One Health approach.

Aquaculture is one of the fastest-growing food production sectors worldwide, especially in low- and middle-income countries. But as aquaculture intensifies to meet global demand, so does the disease burden affecting aquatic animals. Antibiotics are not a long-term solution and tend to be misused without proper training and consultation, often leading to resistant bacteria: a form of AMR. AMR refers to any microbe that develops resistance to the substance designed to control it.

Antimicrobials are given to food-producing animals. Drug-resistant bacteria develop in animals; drug-resistant bacteria can spread in the environment and food, and can be transferred to people by eating food.

Resistant bacteria is a major concern to human, animal and environmental health.

End transcript: Video 9

Video 9

Interactive feature not available in single page view (see it in standard view).

Why should we be concerned about using antimicrobials in (aquatic) animals? For inspiration for your answer, look at the figure that you studied in Activity 17.

To use this interactive functionality a free OU account is required. Sign in or register.

Interactive feature not available in single page view (see it in standard view).

The link between use of antimicrobials in food-producing animals and AMR spread among humans requires further study, because the link isn’t as clear as we think. There is some evidence that use in animals contributes to AMR spread in people, but what isn’t clear is how much it contributes compared to use in human health. Further studies are also required to quantify the volumes of antibiotics used in companion animals compared to food-producing animals. Although we might assume there are much higher volumes of antimicrobials used in food-producing animals, there are limited data available on this point, and even less on the reasons for use (treatment, prophylaxis, growth promotion). This data gap is slowly changing as countries start to improve the ways they measure and monitor the quantities of antibiotics and how they are used in different sectors.

In conclusion, global antibiotic consumption has increased since 2000 and is predicted to continue increase in the future (WHO, 2015b). In some countries, antibiotic use in humans and animals has decreased, but the opposite has happened in others. It is important to remember that any encounter a bacterial population has with an antibiotic may select for resistant bacteria. This is irrespective of whether bacteria are innately resistant or have become resistant due to mutation or gene transfer. The antibiotics kill the non-resistant bacteria, but the resistant bacteria survive. As described above, we don’t yet fully understand the links between use in agriculture and resistance in human disease. There are proven examples of resistant bacteria in animals transferring to humans through the environment and/or the food chain; however, there is a poor understanding of the scale of these events and their impact, and it is likely that, overall, AMR in humans is related to antimicrobial use both in healthcare and in farming. All sectors, therefore, need to address the issue of misuse of antibiotics to do their part in minimising the emergence and spread of AMR.

5 The global response to fight AMR

In the previous section you learned about some of the underlying causes, the global scale and the impact of the problem of AMR. This section introduces steps we can take to address this problem, One Health and global efforts that are currently being made to address the problem of AMR.

After this section you will be able to:

• explain why the problem of AMR needs a One Health approach
• know about ongoing global efforts to address the problem of AMR
• reflect on your own role and those of your colleagues in tackling the problem of AMR.

5.1 What can we do to address the problem of AMR?

The problem of AMR is a universal issue; every one of us could be directly or indirectly impacted by it. AMR already has a significant impact, being responsible for an estimated 700,000 deaths worldwide in 2014 (Review on Antimicrobial Resistance, 2014), and this impact will become increasingly severe if action is not taken now.

In this section you will learn about steps we can and should take to fight the problem of AMR. You will use your understanding of the underlying causes that have led to the global scale of the problem of AMR to reflect on how all these steps are in themselves contributing to fighting it.

Activity 22: Ten things we can do to reduce AMR

Watch Video 10, which shows ten things we can do to reduce AMR.

Download this video clip.Video player: Video 10

Show transcript|Hide transcript

Transcript: Video 10

TEXT ON SCREEN

The 10 steps to reducting AMR according to the Review on Antimicrobial Resistance.

1 Public awareness. Improving global awareness of AMR to reduce use of antibiotics when theyre not needed.

2 Improved hygiene. Focus on improving basic access to water and sanitation, and reduce infectious diseases in hospital and care settings.

3 Reducing antibiotics in agriculture and their dissemination in the environment, as well as use simply to promote growth.

4 Global surveillance of AMR. From levels of drug resistance to consumption of antimicrobials in both humans and animals.

5 Develop rapid diagnostics. Investing in the Global Innovation Fund to revolutionise the way antimicrobials are used.

6 New vaccines and alternatives. Lowering the demand for reactive treatments and renew early research for vaccines.

7 Recognition of hard work. Increasing the numbers of people working in infectious disease, the recognition of those already doing so, and improving pay for important work.

8 Creating a Global Innovations Fund. Supporting early-stage development in a field where public and private R&D is lacking.

9 Incentives for investment. Creating a commercial viable market for antibiotics that will incentivise investment in R&D spending.

10 Collaboration on a global scale. Bringing together global partners including the G20 and the UN to build worldwide support against AMR.

End transcript: Video 10

Download

Video 10

Interactive feature not available in single page view (see it in standard view).

Take a moment to reflect on these ten steps. Pick three steps and, use your understanding of the underlying causes and drivers of the problem of AMR to write down how each of these steps contributes to addressing the problem. If you have difficulty thinking of things you can do, just watch the video again.

To use this interactive functionality a free OU account is required. Sign in or register.

Interactive feature not available in single page view (see it in standard view).

5.2 One Health

In AMR surveillance and you you were introduced to the concept of One Health and why addressing the issue of AMR requires a One Health approach. One Health is defined as ‘the collaborative effort of multiple disciplines – working locally, nationally, and globally – to attain optimal health for people, animals and our environment’ (One Health Initiative Task Force, 2008).

In this module you have learned that antimicrobial-resistant bacteria can be found in humans, animals and the environment. It makes sense, therefore, to take a One Health approach to address the problem of AMR.

Figure 8 Addressing AMR with a One Health approach

Show description|Hide description

A Venn diagram of three circles, labelled ‘Animal’, ‘Human’ and ‘Environment’. The centre, where the three circles overlap, is labelled ‘One Health’.

Figure 8 Addressing AMR with a One Health approach

5.3 International efforts

In Section 3.3 you learned that the UN General Assembly gathered in September 2016 to discuss the problem of AMR.

The 193 member states committed to work collaboratively to take worldwide action to control AMR by signing the UN Declaration on AMR. All the declaration signatories have agreed that drug-resistant infections must be tackled as a priority and have committed to:

• developing surveillance and regulatory systems on the use and sales of antimicrobial medicines for humans and animals
• encouraging innovative ways to develop new antibiotics and improve rapid diagnostics
• raising awareness among health professionals and the public on how to prevent drug-resistant infections.

By taking this course and discussing what you have learnt with colleagues, friends and family, you are already helping to raise awareness of AMR.

Figure 9 Guidance on how to respond to AMR.

Show description|Hide description

This figure shows different international and national collaborations under the One Health approach to address the problem of AMR.

Figure 9 Guidance on how to respond to AMR.

AMR surveillance is critical to tackling AMR, and is the backbone of these efforts. In AMR surveillance and you you learned that AMR surveillance is the ongoing collection, analysis, interpretation and dissemination of data related to AMR.

• At a global level, AMR surveillance provides quantitative data about the spread of resistant strains of bacteria, revealing trends and potentially identifying hotspots of resistant infections.
• At a regional level, surveillance data informs intervention priorities and helps to identify gaps in service delivery.
• At a national level, data guides planning and resource-allocation, and informs policies and responses to patterns and trends.

AMR surveillance data are important to inform policy-makers and decision makers at all levels.

Let’s look at two surveillance programs in the framework of the Global Action Plan on AMR supported by the tripartite collaboration:

Activity 25: The Global Antimicrobial Resistance Surveillance System (GLASS)

Take a look at Figure 10, taken from the 2020 GLASS report (WHO, 2020):

Maximise

Figure 10 International enrolment in different data surveillance systems. (AMR = antimicrobial resistance, AMC = antimicrobial consumption)

Show description|Hide description

This map shows which countries are enrolled in different data surveillance systems; a system to monitor antimicrobial consumption (AMC) at the national level (in yellow) and a system for collection, analysis and sharing of national data on antimicrobial resistance (AMR) in samples collected routinely for clinical purposes for the priority pathogens (in purple), or countries that are enrolled in both systems (in blue) (WHO, 2020).

Figure 10 International enrolment in different data surveillance systems. (AMR = antimicrobial resistance, AMC = antimicrobial consumption)

1. Is your country enrolled in GLASS?
2. If so, is it enrolled for AMR or antimicrobial consumption surveillance, or both?

You will learn more about GLASS in the module An overview of national AMR surveillance.

To use this interactive functionality a free OU account is required. Sign in or register.

Interactive feature not available in single page view (see it in standard view).

6 End-of-module quiz

Well done – you have reached the end of this module and can now do the quiz to test your learning.

This quiz is an opportunity for you to reflect on what you have learned rather than a test, and you can revisit it as many times as you like. 

• End-of-module quiz

Open the quiz in a new tab or window by holding down ‘Ctrl’ (or ‘Cmd’ on a Mac) when you click on the link.

7 Summary

Bacteria are micro-organisms that can cause diseases in humans, animals and plants. Hygiene measures such as handwashing and water sanitation are important in the prevention of bacterial infections. Antibiotics can be used to treat a bacterial infection. Antibiotics are sometimes referred to as ‘magic bullets’ that kill the infection but keep the patient alive. Antibiotics have played an important role in the treatment of bacterial infections, but also have supported modern human and veterinary medicine in different ways. For example, prophylactic use of antibiotics in surgery reduces the risk of infection. Antibiotics also have a role in food production by keeping plants and food-producing animals healthy.

However, due to resistance that develops in bacteria, antibiotics are becoming less effective in treating bacterial infections. Development of resistance is a naturally occurring process, but due to increased antimicrobial use in human and animal health, we have selected for resistant bacteria. The resistant bacteria can spread directly between humans, between animals and humans, and in some cases via the environment.

The increase in AMR is a serious threat to global health. The global response to fight the problem of AMR includes several activities in the framework of the Global Action Plan on AMR, which uses a One Health approach.

Now that you have completed this module, consider the following questions:

• What is the single most important lesson that you have taken away from this module?
• How relevant is it to your work?
• Can you suggest ways in which this new knowledge can benefit your practice?

When you have reflected on these, go to your reflective blog  and note down your thoughts.

8 Your experience of this module

Now that you have completed this module, take a few moments to reflect on your experience of working through it. Please complete a survey to tell us about your reflections. Your responses will allow us to gauge how useful you have found this module and how effectively you have engaged with the content. We will also use your feedback on this pathway to better inform the design of future online experiences for our learners.

Many thanks for your help.

Now go to the survey.

References

Acknowledgements

This free course was collaboratively written by Clare Samson and Dorien Faber, and reviewed by Priya Khanna, Hilary MacQueen, Rachel McMullan,Claire Gordon and Natalie Moyen.

Except for third party materials and otherwise stated (see terms and conditions), this content is made available under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Licence.

The material acknowledged below is Proprietary and used under licence (not subject to Creative Commons Licence). Grateful acknowledgement is made to the following sources for permission to reproduce material in this free course:

Images

Course image: © Design Cells/iStock/Getty Images Plus.

Figure 1: © Natalie Dee 2002–2018. Courtesy of Natalie Dee.

Figure 2: Center for Disease Dynamics, Economics & Policy (cddep.org). © Natural Earth.

Figures 3–5: taken from https://resistancemap.cddep.org/ AntibioticResistance.php.

Figure 7: from Gelband, H. et al. (2015) The State of the Worlds Antibiotics 2015, https://www.cddep.org/ publications/ state_worlds_antibiotics_2015/. Source: Van Boeckel et al., 2015 (adapted; based on IMS MIDAS).

Figure 8: United Nations Foundation (2017) ‘Sustaining global action on antimicrobial resistance’, Wellcome Trust.

Figure 9: Fleming Fund (2017) ‘What you need to know about antimicrobial resistance’, taken from https://www.flemingfund.org/ wp-content/ uploads/ LP1_AMR_A4Screen_FinalSignOff_Jan2017.pdf.

Figure 10: data, World Health Organization; map, Information Evidence and Research (IER). © WHO 2019.

Videos

Video 1: from Pain, Pus and Poison: The Search for Modern Medicines, episode 2, TX 10 Oct 2013. © BBC.

Video 2: ‘The cure – unsung hero: Ignaz Semmelweis’, 20 August 2013.

Video 3: ‘Seven wonders of the microbe world’, The Open University; Alexander Fleming in his laboratory: © Davies/Stringer/iStock/Getty Images Plus; image from Living Memory: Ena Munroe/The Living Memory Association; image of bacteria-MRSA: Centers for Disease Control and Prevention, USA (public domain); image of Penillium notatum : this file is licensed under the Creative Commons Attribution-Share Alike licence, http://creativecommons.org/ licenses/ by-sa/ 3.0/; image of William Stewart: public domain.

Video 4: BBC Learning Zone. © BBC.

Video 6: TED-Ed; this file is licensed under the Creative Commons Attribution-Noncommercial licence (http://creativecommons.org/ licenses/ by-nc/ 3.0/).

Video 7: Michael Mosley vs The Superbugs, TX 17 May 2017. © BBC/Renegade Pictures.

Video 8: TED, 25 June 2015, https://creativecommons.org/ licenses/ by-nc-nd/ 4.0/.

Video 9: WorldFish; this file is licensed under the Creative Commons Attribution-Noncommercial licence (http://creativecommons.org/ licenses/ by-nc/ 4.0/); text: Global action plan on antimicrobial resistance. https://apps.who.int/ iris/ bitstream/ handle/ 10665/ 193736/ 9789241509763_eng.pdf : World Health Organization; [n.d.]. Licence: CC BY-NC-SA 3.0 IGO.

Video 10: The Association of the British Pharmaceutical Industry, ‘10 steps to reducing AMR – the Review on Antimicrobial Resistance’.

Every effort has been made to contact copyright owners. If any have been inadvertently overlooked, the publishers will be pleased to make the necessary arrangements at the first opportunity.