Antibiotic Resistance I

You Don’t Want No Problem

‘You don’t want zero problems big fella!’ – HaHa Davis, 2016

You can’t escape antibiotic resistance in the news, whether as MRSA, the apocalypse pig, or the latest magical drug fêted as crisis bud-nipper. New Scientist predict that ‘antibiotic resistance will hit a terrible tipping point in 2017’; the notoriously reliable Daily Mail screams in 38pt bold that we’re all at risk from the antibiotics apocalypse, but wait! the BBC concurs. All of these superlatives can be a bit exhausting – should we dismiss them as the usual media buzz and scaremongering? After all, there’s been chatter about antibiotic resistance for decades now, and the world rumbles on, right? Unfortunately, this is a very real threat: urgent action is required and complacency is a luxury we cannot afford. The more I read on the subject, the more frightened I become, my thoughts inescapably converging at, ‘Holy fuck we’re fucked.’ But before we can get into any of that, we need to define some terms.

Let’s start simple and build up: what is a microbe? A microbe (Greek mikros for small plus bios meaning life) is a microorganism (literally a small organised thing) is a microscopic lifeform too small to see with the naked eye. This group is extremely diverse, and includes representatives from every branch of the tree of life. Bacteria, archaea, protozoa, fungi, algae, and even tiny animals are included; irritatingly biologists cannot agree on whether viruses are technically alive, but we’ll lump them in with microbes nonetheless. For the most part, microorganisms are useful, performing a wide range of incredible and vital processes that we rely on: they recycle nutrients, make bread, cheese, and beer, and cover nearly every surface of our bodies, keeping us healthy and safe. A small percentage of microorganisms infect humans and cause diseases, and these are called pathogens.

Microbes that can become pathogens
Microbe turned pathogen. Clockwise from top left: Candida albicans, a fungus that lives in healthy intestines but can cause thrush. Zika virus, responsible for the 2015-16 epidemic in Brazil. Plasmodium falciparum, the parasite that causes malaria. E. coli, probably the most famous bacterium, which lives in our guts and helps to keep us healthy; some strains can cause food poisoning.

An antimicrobial, then, is anything that acts against microbes by either (a) stopping their growth and reproduction or (b) killing them outright. Plenty of things can kill a microbe, but they might also kill you: bleach is extremely effective at destroying all manner of nasty germs, but you wouldn’t swallow it to cure a cold. That’s because bleach is a nonselective antimicrobial, a nuclear bomb that causes a lot of collateral damage. More useful are the selective antimicrobials – more like those lovely surgical drone strikes – which act against a specific class of microbe and don’t harm the humans who take them as drugs. For example, Tamiflu is an antiviral medicine used to treat influenza, whereas Canesten cream contains clotrimazole, an antifungal that can treat athlete’s foot.

Please do not drink bleach.
Your common or garden antimicrobial.

Unfortunately for us, microbes have a frustrating knack of developing resistance to our drugs. This means that a microorganism is no longer affected by a drug which previously stopped it growing or killed it – this drug can no longer be used to effectively treat an infection caused by the resistant pathogen. How does this happen? Kurzgesagt produced a very good and remarkably short video explaining the process, but if you’re disinclined to follow links, I will give it a crack. At its heart, the problem is that microbes evolve – in fighting antimicrobial resistance, we are trying to win an unwinnable war against the inexorable force of natural selection. Every species evolves. Mutations, or changes to the sequence of DNA ‘letters’, inevitably accumulate in every organism over time. The biological machines that copy DNA aren’t 100% accurate, so ‘typos’ occur; the repair mechanisms in the cell also make mistakes, like ‘autocorrect’; bacteria can pass DNA between themselves like ‘computer viruses’; chemicals and radiation can directly damage the DNA, like a cat sitting on your keyboard (my metaphor finally breaks down).

The instructions written into DNA are exquisitely complicated, so it’s most likely that a mutation will be bad for the organism, reducing its fitness in the environment and its chances of surviving to pass on its genes. However, every now and then a random mutation happens to improve an organism’s fitness in a particular environment – it might allow a microbe to survive when an antimicrobial is present, for example. In this case, the mutation will be ‘selected for’: while normal microbes are dying, those with the beneficial mutation will be able to reproduce and pass on their genes to their offspring. Before long, the only surviving microbes are those with the mutation that makes them resistant to the antimicrobial, and we have a problem on our hands.

In Through the Looking Glass, the second Alice in Wonderland novel, the Red Queen drags Alice alongside her as they run ‘so fast that at last they [seem] to skim through the air’, but ‘however fast they [go] they never [seem] to pass anything.’ The Red Queen explains this phenomenon:

‘Now, here, you see, it takes all the running you can do, to keep in the same place.’

This idea has been borrowed to explain evolutionary arms races between species, and neatly illustrates the difficulties of fighting an attritional war against pathogens. We spend decades and millions of pounds developing an antimicrobial; a random mutation occurs that makes microbes resistant to the drug; we pour even more resources into coming up with a cunning workaround; another random mutation grants resistance. It’s always just a matter of time until the blind random workings of evolution make our antimicrobials – often the result of long hours, hard work, and keen wits – useless.  

Alice_queen2_1
The Red Queen’s Race – John Tenniel

While this is a problem with all classes of antimicrobials (and indeed anticancer drugs), we’ll narrow our focus to antibiotics, the drugs used to treat bacterial infections. First off, where do antibiotics come from? Microbes live in dense and varied communities – a gram of soil contains billions of bacteria, and hundreds of thousands of different species. Every environment has limited resources, so microbes have evolved to find ways of competing with each other. One excellent way to get ahead of the competition is to produce chemicals that kill them and not you: these chemicals are antibiotics. The vast majority of approved antibiotics were pilfered from nature, especially from fungi and bacteria that embarrass scientists by synthesising fiendishly complex molecules using beautiful chemistry we can only dream of matching.    

Although there are hundreds of different antibiotics, there are very few mechanisms by which these drugs work. To be effective, an antibiotic must interfere with a vital process in the bacterial cell and not cause harm to human cells. Although there are over 200 essential proteins in bacteria – all targets that could be inactivated by a drug  – only three pathways are hit by the vast majority of  antibiotics. The beta-lactam family, which includes penicillins, bind and inhibit proteins required to build the bacterial cell wall. These penicillin-binding proteins (PBPs) cross-link polymer strings to form a strong mesh structure; without these cross-links, the cell wall lacks integrity, and the bacterium bursts and dies. In biology, it is generally true that ‘structure determines function’: the shape of a molecule allows it to do its job. In this case, the penicillin molecule has a similar shape to the part of the cell wall polymer to which the PBP binds. When the PBP binds penicillin, it can no longer perform its vital function, and so the cell wall weakens and the bacterium dies. Other antibiotics target processes such as protein synthesis, RNA synthesis, and production of vitamins.

pen v alaala

Structural comparison of penicillin and a component of the bacterial cell wall
Structure determines function. Penicillins, a common class of antibiotic, work by mimicking the structure of a D-Alanine dipeptide, a key component of the bacterial cell wall which is bound by PBPs. Space-filling and skeletal representations are shown, red is used to highlight regions of structural similarity in the latter.

There are three main routes by which bacteria can acquire resistance to antibiotics. Access of the drug to the target can be cut off, either by stopping the antibiotic from entering the cell or by actively pumping the drug out of the cell. The drug target can be changed by mutation or chemical modification: most antibiotics work by specifically binding their target to prevent its normal function, and even slight changes in the target’s structure can prevent this interaction. Finally, bacteria can produce enzymes that modify the antibiotic itself, either by directly breaking it down or by adding chemical groups that inactivate the drug.

Importantly, once one bacterium has stumbled upon a way to resist an antibiotic, it can spread this capability far and wide with terrifying speed. Humans can only pass on their genes vertically, which means that the transfer occurs from parents to children, down a branch of the family tree. Bacteria are not so limited – they can pass on their genes horizontally to very distantly related species, leaping from one tree to another with ease. This allows bacteria to evolve extremely quickly, and antibiotic resistance genes to be shared around. For example, MRSA likely picked up the mecA gene from a distant relative; this gene encodes PBP2a, a protein that continues to cross-link the cell wall in the presence of penicillins, allowing MRSA to survive exposure to these antibiotics and making infections very difficult to treat. Many resistance genes are carried on plasmids – small, circular pieces of DNA which can be easily passed between bacteria. 

Term Definition
Microbe/Microorganism

A microscopic living thing.

Bacteria

Bacteria are an extremely large and diverse group of microbes which have no nucleus (the part of the cell containing DNA in, for example, humans). Bacteria are very small, adapt very quickly, and live practically everywhere. Some examples are E. coli and Staphylococcus aureus.

Pathogen

An organism that causes disease – e.g. Mycobacterium leprae causes leprosy.

Antimicrobial A chemical that either stops a microbe from growing and reproducing or kills it altogether.
Antibiotic A chemical that acts as an antimicrobial specifically against bacteria.
Resistance

A microbe is susceptible to an antimicrobial if the drug stops it growing or kills it. A microbe can become resistant to a drug through natural selection, in which case it will no longer be affected by the drug.

Plasmid

A small circular piece of DNA containing several genes. It can be easily passed between bacteria of the same or different species. Often plasmids contain genes that allow a bacterium to become resistant to antibiotics.

Lateral Gene Transfer

The process of passing genetic information between bacteria instead of from parent to offspring. Bacteria can take up DNA from the environment (transformation), move plasmids between themselves (conjugation), or move DNA between themselves via a virus (transduction). LGT allows more rapid spread of resistance genes, and spread between distantly related species.

Now that we understand what antibiotic resistance is, we can examine the consequences of this phenomenon. To argue the need for action, scientists have imagined what a post-antibiotic era might look like – a world in which we no longer have any effective antibiotics. When was the last time you took these drugs? Maybe you had strep throat a couple of years ago, and while you were grateful for the prescription then, antibiotics don’t seem all that important. It might not feel like a problem that will affect you – you’re not old or frail, you’re hygienic, you rarely get ill – in fact, it feels suspiciously like someone else’s problem. But antibiotic resistance will affect everyone. Modern society revolves around these drugs, and if we lose them it will feel as though the world has stopped spinning.

Most obviously, we will be unable to treat bacterial infections. Sally Davies, the UK’s Chief Medical Officer, noted in her 2011 report that infectious diseases ‘represent the greatest cause of death and burden of disease’ globally. Although improvements in hygiene, sanitation, and vaccination have dramatically reduced the mortality rates of infectious diseases in developed countries, they are still a major cause of death for the very young and elderly – in 2010, they accounted for 7% of deaths in England. As our most effective weapons against these diseases are blunted, we can expect this percentage to drastically spike. Davies also warns that ‘older diseases which we managed to control are re-emerging as they become resistant to our antimicrobial drugs.’

Antibiotics have been so successful that many historically deadly diseases are now nothing to worry about. In 1920s America, the most common cause of death in 5-20 year olds, and second most common cause in 20-30 year olds, was rheumatic fever. If you’re like me, you haven’t heard of this disease, because it is now extremely rare in the the developed world: fewer than 0.001% of people in the UK are afflicted with it. In 2017, rheumatic fever is easy to treat with antibiotics; an expert on the disease admitted that to today’s medical students, discussing it ‘seems irrelevant.’ But less than a century ago, the only treatment was aspirin and bed rest; most patients were ill for months and forced to stay at home; often the disease would attack the heart, causing lifelong damage, strokes, heart failure, and even death.

What terrible, rare bacteria wreaked this carnage? Streptococcus species that live on our skin and cause common infections like tonsillitis or strep throat. I had strep throat a couple of years ago – I think I caught it after spending a few consecutive nights sleeping on friends’ floors after going out. It ruined my romantic getaway to Paris by triggering a declension from dashing lothario to mewling mess: I couldn’t swallow without pain, had to stop eating, and became generally pathetic. But I got home, took some antibiotics, and within a week I was Casanova reborn. Imagine a world in which such a trivial infection led to heart failure – hundreds of thousands of Streptococcus infections happen in the UK every year.

Add to this meningitis, diphtheria, gonorrhea, syphilis. Pneumonia used to kill 0.1 – 0.2% of the US population every year – between 1900 and 1937, it was consistently either the first or second most common cause of death. Tuberculosis (TB) vied for first place: strains have now emerged that are resistant to isoniazid and rifampicin, our two most powerful anti-TB drugs. A TB strain has arisen in India that is totally resistant to all antibiotics. If resistant TB becomes widespread, we may have to resort to isolation even in the UK; a patient’s 1944 diary from a tuberculosis sanatorium should be evidence enough of how terrible a prospect that is.

If you’re sexually active, antibiotic resistance is not your friend: in 2015 there were over 400,000 new STI diagnoses in England, and young people are far more likely to be infected, accounting for nearly two thirds of chlamydia and half of gonorrhoea cases. The latter is particularly worrying, as class after class of antibiotic has lost the ability to treat gonorrhoea in the past decade: high levels of resistance to the final effective antibiotic class – cephalosporins – have been reported since 2011, and there are currently no drugs to replace these. Many people infected with gonorrhoea show no symptoms, but if the disease is left untreated, it can lead to infertility and life-threatening infection. Never go in without a skin, eh?

TB

But we need antibiotics for so much more than treatment of bacterial infections. Modern healthcare is built on the basis that antibiotics can not just treat, but prevent infections. Your skin is really good at preventing the access of pathogens to the more vulnerable parts of your body – it’s your first line of defence. Many medical procedures involve breaking this barrier with a scalpel. In the UK, there are nearly 800,000 hip replacements every year; nearly one in a thousand UK residents require invasive treatment because their kidneys aren’t working normally; every year at least 48,000 Britons experience major trauma, often due to road accidents. Treatments for several common illnesses involve immunosuppression: the immune system, our natural defence against pathogens, must be dampened for organ transplants and cancer therapy to work. In 2014, an average of 980 UK residents were diagnosed with cancer every day; in 2015, 2.5 million people in the UK were living with cancer; currently, it is estimated that half of the UK population will develop cancer at some point in their lives. Chemotherapy kills cancer but stifles your immune system, leaving you vulnerable to bacterial infections – antibiotics are essential to treat the disease.

Do you think you’ll ever consider having children? Before antibiotics were introduced, 0.5% of women died during childbirth (think of all of those poor mothers in Brontё novels) compared to 0.009% today. There were almost 700,000 live births in England and Wales in 2014: without antibiotics, 3,500 of those mothers might have died. Caesarean sections are even more reliant on antibiotics, and growing in popularity, from one in ten births 30 years ago to one in four today. If you can still stomach TED talks, Maryn McKenna describes a world without antibiotics in her 2015 speech:

‘More than anything else, we’d lose the confident way we live our everyday lives. If you knew that any injury could kill you, would you ride a motorcycle, bomb down a ski slope, climb a ladder to hang your Christmas lights, let your kid slide into home plate?’

Antibiotic resistance could rob us of our freedom. One in five British adults have a tattoo – would you let someone puncture your best defence against bacteria with a grubby needle if an infection could end your life? All of us stand to lose in a world without antibiotics. 

How likely is this scenario though? Is it anything more than alarmist science fiction? At the start of this post, I listed a few examples of media headlines that seem overblown; now let’s look at a few quotes from more reputable sources:

‘A new report by WHO… reveals that this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance… is now a major threat to public health.’Press Release, WHO, 2014.

 

‘A post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century… Very high rates of resistance have been observed in all WHO regions in common bacteria.’Antimicrobial Resistance: Global Report on Surveillance, WHO, 2014.

 

‘If we are not careful, we will soon be in a post-antibiotic era, and for some patients and for some microbes, we are already there.’Dr Tom Frieden, CDC Director, 2013.

 

‘Resistance to antibiotics… is the greatest and most urgent global risk… Due to antimicrobial resistance, many achievements of the twentieth century are being gravely challenged.’UN General Assembly on Antimicrobial Resistance, 2016.

In 2014, then Prime Minister David Cameron commissioned a very welcome report into antimicrobial resistance, headed by economist Jim O’Neill. O’Neill is a former Goldman Sachs chairman, and has no scientific qualifications, but Cameron’s choice was – as much as it pains me to say it – a brilliant one. A year earlier, the UK Department of Health requested a rapid review on the cost of antimicrobial resistance, but health economists Coast and Smith found themselves frustrated by the state of the field. The few studies they uncovered gave inaccurate estimates of economic impact because of their limited scope: ‘none of the studies considered the bigger picture – a world with no effective antibiotics for situations where they are currently used routinely.’

This is problematic because ‘evidence-based policymaking prioritises health problems by economic burden and cost effectiveness of interventions’ – the government won’t act to tackle a problem unless it is shown that failing to act will be very expensive. Even though scientists were sounding the alarm about the dangers of antimicrobial resistance, health economists had failed to show that it ‘costs enough to be a health priority.’ The highest estimate for the cost of resistance that Smith and Coast found was $55 billion per year – to you and I this sounds disastrous, but this figure only places tenth in the annual cost of illnesses to the USA, behind heart disease, substance abuse, and Alzheimer’s. The authors called for ‘full health system analyses’ and ‘a change in culture and action… to plan for a world with more antibiotic resistance.’

Enter Jim O’Neill. His first move was to commission two research teams at RAND Europe and KPMG to assess the future impacts of antimicrobial resistance on ‘the health and wealth of nations’ if no action were taken. Their findings are staggering:

‘Initial research, looking only at part of the impact of AMR, shows that a continued rise in resistance by 2050 would lead to 10 million people dying every year and a reduction of 2% to 3.5% in Gross Domestic Product (GDP). It would cost the world up to 100 trillion USD.’

However, O’Neill notes that these figures ‘do not capture the full picture of what a world without antimicrobials would look like’ – as we examined above, we rely on these for  far more than treating infections. The team looked at four of the most common medical procedures that depend on antibiotics – Caesarean sections, joint replacements, cancer therapy, and organ transplants – and found that together they contribute 4% to the world’s GDP, worth $120 trillion from now until 2050. These procedures ‘allow people to live active lives for longer… and stay in the workforce’, but might become too risky without antibiotics.

Screen Shot 2017-06-22 at 21.59.57
Predicted deaths due to antimicrobial resistance by 2050 if no action is taken.

The report concludes that ‘even on a strictly macroeconomic basis it makes sense for governments to act now’ because ‘the cost of dealing with resistance is far smaller than not taking action.’ RAND Europe’s research found that ‘delaying the development of widespread resistance by just 10 years could save 65 trillion USD of the world’s output between now and 2050.’ This is perhaps a cold blooded way of looking at the problem, but this is how governments think. O’Neill’s report has been pivotal in spurring global discussion and action; we’ll come back to it in a later post.

Screen Shot 2017-06-22 at 22.03.58
The predicted effect of antimicrobial resistance on the world economy by 2050 if no action is taken.

Antimicrobial resistance is happening now. The CDC estimate that ‘each year in the United States, at least 2 million people acquire serious infections with bacteria that are resistant to one or more… antibiotics’, and ‘at least 23,000 people die each year as a direct result of these antibiotic-resistant infections.’ A strain of Klebsiella pneumoniae resistant to all the antibiotics we have killed a woman in Nevada in September 2016. Four years ago, an elderly man with prostate cancer was found to have E. coli resistant to nearly all antibiotics growing in his rectum, and doctors decided not to remove his tumour because of the risk of infection. Already we’re being forced to make tough decisions about routine medical procedures.

This is our problem to deal with now – but how the hell did we end up in this mess, and how can we get out of it? Watch this space for parts II and III. 

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s