Antibiotic Resistance is Way Worse than You Think...

Imagine a world in which existence itself is so fragile that something as simple as a superficial wound, or a droplet of saliva expelled in a bout of cough could lead to death, sometimes swift, sometimes slow and painful.

Now imagine a world in which science is so advanced that a short course of treatment could wipe out an invisible, yet deadly invasion taking hold of your body.

We don’t need to push our imagination too far. As a species, we have experienced both worlds.

One in which harmful bacteria could invade our defenceless bodies, corrupting our bloodstream and organs. One in which a microorganism such as yersinia pestis could ravage three continents in the XIV century, wiping out up to half of the population of Asia, Africa and Europe. Or in which badly cleaned wounds could lead to septicaemia, claiming more casualties on the battlefield than spears, muskets, rifles and bayonets.

And then we had a new world, the result of advances in pharmacology and medicine which gave us powerful antibiotic drugs, effectively stemming bacterial infections which had been the scourge of humanity for millennia.

And yet, our species is currently facing a lethal challenge, a sword of Damocles hanging over our heads.

The first world is at risk of making a comeback, heralded by the spectre of antibiotic resistance.

10 Million Lives

Let’s begin with some definitions.

First things first: what are bacteria? Bacteria are unicellular microorganisms, they are found almost everywhere, and are vital to our planet’s ecosystems. There are friendly bacteria, but there are also harmful ones. The latter kind may multiply so quickly that they overwhelm host tissues, disrupting their normal function. Or they may outright kill healthy cells, sometimes by secreting toxins. In other cases, bacteria may cause a disproportionate reaction by our own immune system, in itself harmful.

Across millennia, bacterial infections have proven to be amongst humanity’s deadliest foes, a scourge more widespread, exacting and cruel than war, famine or natural disasters.

Yersinia pestis, the bug responsible for the bubonic plague pandemic, killed up to 75 million people over the span of seven years in the XIV century.

Vibrio cholerae, endemic in areas with poor sanitation, was responsible for 40 million deaths in the XIX century alone.

And then there is the worst killer of all: the Mycobacterium causing tuberculosis, a stubborn enemy of our species which may have claimed up to 1 billion lives to date.

These are just three examples of the many deadly diseases caused by bacteria, which are believed to be the main cause of death in history up to the 1940s — when the use of antibiotic drugs became widespread.

The first natural antibiotic was penicillin, discovered by Sir Alexander Fleming in 1928, a truly revolutionary achievement. The National Bureau of Economic Research estimates that the introduction of this drug immediately reduced mortality rate in penicillin-sensitive infection cases by 58%!

Since the introduction of penicillin, antibiotic drugs have become the most common form of treatment against bacterial infections — alongside vaccines, of course, used for the prevention of most widespread bacterial strains.

Some antibiotic drugs may act by stemming the proliferation of bacterial cells, thus containing the infection. Others, known as ‘bactericidal antibiotics’ kill the harmful microorganisms outright, for example by disrupting the formation of the bacterial cell wall.

However, these treatments proved from an early stage that they were far from being a silver bullet. As early as 1945, in his Nobel Prize acceptance speech, Fleming himself warned about the dangers of bacterial resistance caused by an inappropriate use of penicillin.

Which takes us to the next definition: what is antibiotic resistance exactly?

This can be defined as a scenario in which bacteria evolve, developing resistance mechanisms against commonly used drugs, thus making infections more difficult to cure and increasing the risk of outbreaks, serious illness, and death.

In other words: bacteria are living, fast-evolving micro-organisms, which over time can develop defences or immunity against the weapons we use to kill them.

More precisely, these microbes, from the least worrying to the most harmful, have proven an ability to develop resistance genes, which can then easily and quickly spread around the world. In some cases, such resistance genes can be transmitted among different species of bacteria!

Bacterial resistance is definitely one of the most urgent problems faced by modern medicine worldwide, but especially in developing countries in Africa and Asia. In these countries, pathogens transmitted via poorly cooked or preserved food appear to have developed a total immunity even against multi-drug treatments.

Food-borne diseases are not the only worry, however, and common infections such as pneumonia, gonorrhoea, tuberculosis and septicaemia are becoming increasingly difficult to treat. Nowadays, more than 70% of all pathogenic bacteria are estimated to be resistant to at least one commercially available antibiotic.

As stated by Dr David Chinemerem Nwobodo, Renaissance University, Enugu, Nigeria in a 2022 paper:

‘We are rapidly approaching a post-antibiotic era in which common infections and minor injuries can kill again unless immediate and proactive action is taken.’

According to a 2019 report by the US Centres for Disease Control and Prevention, or CDC, more than 2.8 million cases of antimicrobial-resistant infections occurred in the States, which resulted in more that 35,000 deaths. The costs to the public healthcare sector are substantial, estimated at more than $4.6 billion annually.

The Global situation is no less concerning. A study released by medical journal The Lancet in 2019, revealed that antimicrobial resistance was directly responsible for the death of 1.27 million people in that year alone, and was associated with a total of 5 million deaths.

In 2021, the World Health Organisation, or WHO flagged bacterial resistance as one of the top 10 public health threats worldwide. Infections immune to antibiotics are projected to claim up to 10 million lives per year by 2050. In addition to this grim balance sheet, resistance will exact a hefty bill on the global economy. The World Bank estimates that bacterial resistance may result in $1 trillion additional healthcare costs by 2050.

Furthermore, by the year 2030 it could result in GDP losses of up to $3.4 trillion per year.

As is often the case with public health emergencies, low- and middle-income countries are the most affected ones.

To quote again from Dr Nwobodo, this is due to, among other factors:

‘poor-drug quality, insufficient surveillance … poor-healthcare standards, malnutrition, chronic and recurring infection, and the inability to afford more effective and costly drugs’

Resistance Against all Odds

We already hinted at the reason behind this creeping catastrophe: the ability of certain bacterial species to develop resistance genes.

But what exactly causes this type of resistance? The answers are manifold, and not all possible causes have been identified to this day.

The first, obvious culprit, was already pinpointed by Sir Alexander Fleming in his Nobel acceptance speech: the misuse, overuse and abuse of antibiotics. Not only in humans, but also in farm animals.

To clarify: bacterial populations can undergo genetic mutations which make them impervious to attacks delivered by antibiotic drugs. In other words, they develop Antibiotic Resistance Genes, or ARG.

ARGs themselves were believed to derive mainly from de novo mutations, that is, recent mutations triggered by the presence of antibiotics themselves. While these mutations may occur, researchers such as Matthew Stracy, from Oxford University and Israel Institute of Technology, point out that:

‘Selection for existing resistant strains rather than de novo evolution is the predominant mechanism of treatment-induced emergence of resistance’

Allow me to clarify this complex point.

Fact is, many microorganisms possess inherent, inbuilt resistance mechanisms. These were around long before penicillin and other antibacterial agents were discovered.

Known as ‘primary resistance’, these mechanisms emerge from a spontaneous mutation. The frequency of such spontaneous mutations is low, but once you throw an antibiotic into the mix, there is a shift in the balance of power. The antibiotic kills the majority of the non-mutated bacterial population, and now the ‘mutants’ have an advantage over the survivors. Thanks to their resistance genes, they can quickly proliferate and spread to other hosts.

With successive generations, the once minority mutants will replace the previous strains, which were more vulnerable to drugs. On the other hand, the development of antibiotics cannot keep up with this evolutionary arms race — and we keep on throwing blunt weapons against enemies who are increasingly aggressive, skilled, elusive and well-armoured!

To quote just an example: the antibiotic ciprofloxacin was licensed as a treatment against Escherichia Coli, among other pathogens. According to the WHO, after the licensing of this drug, E. Coli proved resistant in 8.4% of cases. So, more than 90% of patients were effectively treated. Not bad at all! But over time E. Coli has evolved into a much deadlier foe, and now it can resist ciprofloxacin in 92.9% of cases!

Another worrying example involves the bacterium Staphylococcus, a common pathogen in both humans and animals, responsible for infections of the skin, mucosae and other soft tissues. Staphylococcus infections are particularly common and insidious in hospital settings, when they infest surgical wounds.

Now, Staphylococcus was once sensitive to good old penicillin. But over time it developed resistance against natural penicillins, mainly as a result of antibiotic treatments in livestock. It makes sense that intensive farmers worldwide wish to protect their large herds of animals against infection, but overuse of penicillins in this setting caused the emergence of mutated Staphylococcus strains, equipped with a clever defence mechanism: the production of a protein, called PBP2a, which binds to the antibiotic molecules rendering them harmless.

In the 1970s and early 1980s, penicillin-resistant strains of Staphylococcus first became widespread in humans, mainly in hospital settings. These prompted researchers to develop new, artificial stronger types of penicillinic drugs, able to circumvent the PBP2a defence. The weapons race is still on!

In recent years, the Covid-19 pandemic has further contributed to exacerbating antibiotic resistance. Almost 7% of all Covid diagnoses were associated with a concomitant bacterial infection, leading to a higher use of antibiotics in hospitals. A higher use which, again, takes resistance one step further.

Moreover, a multicentre study conducted in the US revealed that 72% of Covid patients were misdiagnosed and misprescribed antibiotics — another factor enhancing defence mechanisms amongst bacterial strains.

Rats and Squirrels

The scary part is that resistance genes can be transferred horizontally: they can break the species barrier, and jump from one type of bacterium to another. This Horizontal Gene Transfer, or HGT, can occur also between ‘environmental bacteria’ — such as the ‘good’ kind living in your gut — and the pathogenic kind. And research has shown that the transfer of genetic material can be induced by ‘stressor’ elements, such as, well, antibiotics!

This is what happens in the not unfamiliar situation in which patients are mis-prescribed an antibiotic treatment. Maybe they are suffering from a viral infection: in that case, the drug they receive will do absolutely nothing against their virus; but it may harm the ‘friendly’ bacterial flora, killing off a part of it, while sparing those bacteria which are immune to the drug — setting the stage for Horizontal Gene Transfer.

Let’s recap this rather convoluted explanation with a metaphor.

Let’s pretend that your garden is home to a colony of rats, who chew on your broadband cables, steal your food and in general make your life a misery. And these rats coexist with a family of friendly squirrels, who leave hazelnuts on your windowsill and jump on your shoulder when you break into a song.

You then decide to litter your garden with traps to get rid of the vermin. After initial success, a minority of rats survives. They are genetically predisposed to, well, smell a rat, and dodge your traps. These rats will proliferate, making a mockery of the now useless traps you will keep throwing at them!

Now, let’s pretend that the garden in question is inhabited only by friendly squirrels, but you somehow decide to litter the grounds anyway with your killing contraptions. This will enact a mass murder of the cute critters, but some of them will survive. When the rats will eventually rock up in your backyard, the surviving squirrels will transfer to the vermin their innate ability to dodge the killing machines.

OK, maybe the metaphor is not entirely fitting, but I hope I made my point clear: play it easy with the traps, lest you find yourself doubly, totally screwed.

So, we have identified abuse of antibiotics as the main guilty party, but it may not be the only one, as suggested by recent research.

In October 2022, Doctor Xingdong Shi, at the Centre for Technology in Water and Wastewater, University of Technology, Sydney, published a chilling piece of research. Dr Shi first points out that antibiotic-resistant bacteria are rife in water reservoirs:

‘In many cases this is because human excreta are a source of both antibiotic and resistance.’

Translated in trivial English: when you take a load of antibiotics, and then take a leak, your pee will eventually make it to bacteria swimming in our waters, perpetuating the cycle of resistance.

Which is scary enough to begin with. But Shi’s paper adds another worrying point. It appears that ‘Many non-antibiotic chemicals have recently been demonstrated to promote the transfer of ARGs (Antibiotic Resistant Genes) such as metallic nanoparticles, microplastics and some other pollutants … The previous reports in observation of enhanced spread of ARGs by non-antibiotic conditions raise an intriguing and profound question about the role of contaminants other than antibiotics in spreading ARGs.’

Going back to our rodent-based metaphor: according to Dr Shi, it’s not only your traps that will eventually create an army of invulnerable vermin. But even the presence of incorrectly disposed trash in your yard, or even environmental pollution may spawn generations of buff, aggressive critters.

Can We Crush the Resistance?

With this disaster looming ahead, what can we do to defend ourselves against the new generations of resistant bacteria? The first, obvious answer would be to develop new drugs to throw at them!

The problem, though, is that pharmaceutical research requires loads of money, the average cost of bringing one new molecule to market being $1.3 billion. This is a huge investment at a huge risk, as there is no guarantee that a new drug, however promising, proves to be efficacious and safe enough when it reaches the stage of Phase III trials. When it comes to developing antibiotics there is an added risk: a new treatment might be efficacious at first, but it may later encounter resistance!

A 2021 report by the US congressional budget office states this point very clearly:

‘It is pertinent to state that the problem of antimicrobial resistance is aggravated by the lack of interest by pharmaceutical industries in new antimicrobial investment, as they view research for new antimicrobials as “low profit” and believe that resistance will develop for new antimicrobials sooner or later.’

Hence, pharma companies may not be willing to invest in this field, diverting research to other therapeutic areas, such as oncology, metabolic disease and chronic ailments.

The state of antibiotic research might not be so catastrophic, however. We interrogated the online database of clinical studies, ClinicalTrials.gov to assess the research pipeline in the fight against bacterial infections. As of December 2023, there are 337 Phase III studies worldwide, assessing new antibiotic treatments, all of which present promising results and may reach our hospitals and pharmacies in the near future. A further 505 trials are in Phase I and II, hinting at a quite ‘healthy’ pipeline.

However, it could be argued that these future drugs may encounter the same fate as the current one, and eventually lose their battle of wits with mutated bacteria.

So, it makes sense for researchers and governmental authorities to look for alternative solutions.

One possible strategy is to increase infection control efforts within the community and hospitals, such as encouraging hand washing, immunisation with vaccines and cleaning of surfaces and medical implements. A 2019 CDC report noted that such efforts contributed to the reduction of hospital deaths due to bacterial resistance by 30%.

Also in 2019, the European Union enacted legislative measures to reduce or eliminate the addition of antibiotics to livestock feed — thus stemming resistance via controls on the food chain.

When it comes to innovative treatment regimens, a promising alternative is the use of bacteriophages, or phages: these are viruses which infect only bacterial cells. These phages are basically everywhere, in fact they are considered as the most numerous biological agents on earth!

These friendly killer viruses can be introduced into an infected organism at low concentration. They will then proliferate, attack and infect only the bacterial cells, causing no harm to the human host — which sounds awesome! They essentially behave like an army of tiny SAS operators who infiltrate a building and surgically take out the terrorists without harming the hostages!

There are a couple of snags, however.

First, it appears that certain bacteria may spontaneously mutate to develop resistance to phages. Phage-resistant bacteria have been observed in up to 80% of in-vitro studies, simulating intestinal and blood infections. Potentially, though, this resistance may be overcome by the application of ‘phage cocktails’. If the terrorists in question know how to fight off the SAS, you also deploy the SBS, the Delta Force and the SEALs!

But I stress ‘potentially’.

You see, the second snag when it comes to phages is the dearth of extensive research, due to a lack of regulatory guidance standards and robust clinical trial protocols. In other words, we are yet to develop the right framework to conduct large-scale phage studies.

According to a 2019 paper by biotechnologist Danitza Romero-Calle, State University of Feira de Santana, Brazil, human application of phages has been limited to small-scale series of case studies. The routine use of these therapies is currently limited to Georgia, Poland and Russia, with strictly limited use in France for patients with extreme cases of drug-resistant infections.

Rise of the Machines

Phages may be the answer of the future, but science never sleeps, seeking other alternatives.

A promising and fascinating strand of research is centred around the use of machine learning, defined as the:

‘Use and development of computer systems that are able to learn and adapt without following explicit instructions, by using algorithms and statistical models to analyse and draw inferences from patterns in data.’

In February 2022, the already quoted Mathew Stracy and his team at the Israel Institute of Technology published some encouraging results, based on the use of such methods.

Their starting point was the discovery that antibiotic resistance was seldom caused by unpredictable, de novo mutations resulting directly from treatment. Instead, it derived more typically from strain or species replacement, resulting from mutations occurring naturally.

They further observed that certain strains recurred in the same patient, even after several years.

Therefore, they hypothesised:

‘That patients with a history of infections with strains resistant to a given antibiotic are at higher risk of gained-resistance recurrence after susceptibility-matched treatment with that antibiotic’

In other words, their assumption was that the emergence of resistance in individual, specific patients, could be predicted! Next, they developed machine learning algorithms to generate a personalised antibiotic recommendation for each patient in their study, selected among those suffering from Urinary Tract Infections — UTIs — or wound infections.

Then, for each recommended antibiotic drug, they trained a:

‘Logistic regression model’

Which was able to predict the risk of resistance. The model was fed with patient variables such as demographics, risk factors, record of prior infections and, very importantly, previous occurrences of bacterial resistance. This last variable is key:

‘As most infections are seeded from a patient’s own microbiota, these resistance-gaining recurrences can be predicted using the patient’s past infection history’

And now, for the results!

Dr Stracy and his team chose for each patient the antibiotic with the lowest risk of emergence of resistance, as predicted by their machine learning models. The treatments selected with this method reduced the:

‘overall risk of emergence of resistance by 70% for UTIs and 74% for wound infections compared with the risk for physician-prescribed treatments’

How awesome is science?

Conclusion

Antibacterial resistance is a clear and present danger, the result of an evolutionary struggle pitting homo sapiens against mindless single cell organisms, with an apparently unstoppable will to survive and to harm. What is worse, this public health concern is only one facet of a larger issue, antimicrobial resistance. Bacteria are not the only microscopic beings infecting our tissues: viruses, fungi, parasites and other microbes all want a place at the table inside our bodies. Where possible, modern medicine has developed efficacious vaccines and treatments against most of them, but — as is the case with bacteria — also these foes have eventually developed some levels of resistance.

Are we heading to a future similar to our past, one where endemic infections exact a constant toll on our loved ones? Or where sudden, sweeping pandemic outbreaks leave cities depopulated?

The risk is always there, of course.

But, if we are allowed a glimmer of light, our species has progressed by leaps and bounds since the times when tuberculosis ran rampant. We have benefitted from astounding achievements in sanitation, hygiene, prevention and infection control. Recent discoveries have shown that we can enrol phage viruses and machine learning to our cause.

The fight is still on, but we have good reasons to hope.

Key Takeaways

• Antibiotic resistance is a growing threat, with bacteria evolving to resist common treatments.
• Misuse and overuse of antibiotics in humans and animals are primary drivers of resistance.
• Resistant bacteria can spread through horizontal gene transfer, even between different species.
• Innovative solutions like bacteriophages and machine learning are being explored to combat resistance.
• Global efforts in infection control and regulation are crucial to mitigate the spread of resistant bacteria.

Frequently Asked Questions

What is antibiotic resistance?

Antibiotic resistance is a scenario in which bacteria evolve, developing resistance mechanisms against commonly used drugs, thus making infections more difficult to cure and increasing the risk of outbreaks, serious illness, and death.

How many deaths were caused by antibiotic-resistant infections in the US in 2019?

In 2019, more than 2.8 million cases of antimicrobial-resistant infections occurred in the US, resulting in more than 35,000 deaths.

What are the main causes of antibiotic resistance?

The main causes of antibiotic resistance include the misuse, overuse, and abuse of antibiotics in humans and farm animals, as well as the presence of non-antibiotic chemicals that promote the transfer of antibiotic-resistant genes.

How does antibiotic resistance develop in bacteria?

Antibiotic resistance develops in bacteria through genetic mutations that make them impervious to attacks delivered by antibiotic drugs. These mutations can occur spontaneously or be triggered by the presence of antibiotics, leading to the development of antibiotic resistance genes (ARGs).

What is the projected number of deaths due to antibiotic-resistant infections by 2050?

Infections immune to antibiotics are projected to claim up to 10 million lives per year by 2050.

What are some alternative solutions to combat antibiotic resistance?

Alternative solutions to combat antibiotic resistance include increasing infection control efforts, using bacteriophages (viruses that infect only bacterial cells), and employing machine learning to predict and personalize antibiotic treatments.

How can machine learning help in the fight against antibiotic resistance?

Machine learning can help by predicting the risk of resistance emergence in individual patients based on their infection history and other variables. This allows for personalized antibiotic recommendations that reduce the overall risk of resistance.

What is the role of bacteriophages in treating bacterial infections?

Bacteriophages, or phages, are viruses that infect only bacterial cells. They can be introduced into an infected organism to proliferate and attack bacterial cells without harming the human host, potentially overcoming resistance issues.

What are some of the economic impacts of antibiotic resistance?

Antibiotic resistance is estimated to result in $1 trillion additional healthcare costs by 2050 and GDP losses of up to $3.4 trillion per year by 2030.

What is the current state of antibiotic research and development?

As of December 2023, there are 337 Phase III studies worldwide assessing new antibiotic treatments, with an additional 505 trials in Phase I and II, indicating a healthy research pipeline.

Sources

• Original Into the Shadows video: Antibiotic Resistance is Way Worse than You Think…
• https://www.mdpi.com/2079-6382/11/8/1079
• https://www.cdc.gov/drugresistance/national-estimates.html
• https://www.cdc.gov/drugresistance/actions-to-fight.html
• https://www.cdc.gov/drugresistance/intl-activities/tatfar.html
• https://onlinelibrary.wiley.com/doi/abs/10.1002/jcla.24655
• https://www.sciencedirect.com/science/article/pii/S0043135422010065
• https://www.science.org/doi/abs/10.1126/science.abg9868
• https://www.sciencedirect.com/science/article/pii/S2468584423000521https://arxiv.org/abs/2307.14790
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784059/#:~:text=Compared%20to%20antibiotics%2C%20only%20a,may%20adsorb%20to%20individual%20bacteria
• https://academic.oup.com/clinchem/article/58/8/1182/5620739
• https://clinicaltrials.gov/search?intr=Antibiotic%20treatment&aggFilters=docs:prot,funderType:industry,phase:3,results:with,studyType:int
• https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance#:~:text=A%20growing%20number%20of%20infections,medical%20costs%20and%20increased%20mortality
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/
• https://www.who.int/health-topics/antimicrobial-resistance
• Hero image source by WFP/Abubaker Garelnabei / openverse, by.

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