When the drugs won't work: The ongoing journey toward an antibiotic-resistant future
You'd forgive me for feeling a futility for 'recycling' his coffee cup - when, for every cup of coffee consumed about one square inch of rainforest is destroyed - in a world that is overheating and where imminent ecological collapse looms closer with each sip I take.
It's too easy to be numbed by the rhetoric surrounding modern-day catastrophic events. And where next should we be focusing our efforts when there are so many disasters looming before us.
This is not to make light of our plight. We have an individual responsibility of course – please rest assured I will recycle that coffee cup - but save your despair because, unless we can muster some collective responsibility, pretty soon we may not have to worry so much: 'Superbugs' could easily wipe us all out long before anything else comes to pass.
Perhaps the most pressing issue and what we should be most alarmed about right now, is the rapid global spread of multi- and pan-resistant bacteria: The so-called 'superbugs' which cause infections that simply aren't treatable with existing antimicrobial medicines, such as antibiotics.
As I tune in to the BBC Radio 4 news, Health officials are reminding the public not to use antibiotics unnecessarily this winter because of concerns they're becoming less effective.
In a report published today (17th November, marking the start of WAAW – World Anti-biotics Awareness Week), The UK Health Security Agency says one in five people who caught an infection last year had one which was resistant to antibiotic treatment.
Drug resistance at an alarming pace
The World Health Organisation describes anti-microbial resistance (AMR) as one of the most urgent health threats of our time. According to the UK government's AMR review, the global burden of infections resistant to existing antimicrobial medicines is now growing at an alarming pace. Drug-resistant infections are already responsible for more than 700,000 deaths globally each year.
Without effective antibiotics, the world will no longer be able to fight many common bacterial infections, making takenfor-granted procedures like caesarean-section births, organ transplants, joint replacements and many cancer treatments simply unviable. In a post-antibiotic world, even a simple cut may have dire consequences.
Former UK Prime Minister David Cameron said, "If we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work, and we are cast back into the dark ages of medicine." But the unthinkable is happening.
The United Nations now considers superbugs one of the biggest global public health concerns of the 21st century. Today, experts predict that if current practices are allowed to continue 10 million people will die each year from resistant infections by 2050.
Across the world, intensive animal production systems have come to rely on the regular use of antimicrobials to maintain health (and in many instances productivity) in poultry and pig production. Strong legislation has been imposed in many countries especially in Europe. Zinc Oxide for pigs is soon to be banned in Europe and the UK.
Aquaculture is not excluded, but its use of antibiotics is for disease scenarios and not for growth promotion. But notwithstanding, between 2010-30, the global consumption of antimicrobials is predicted to increase by 67 percent from around 63,000 tonnes to an estimated 105,000 tonnes.
Up to a third of the expected increase in livestock is based on a prediction that routine use of antibiotics for disease prevention - or growth promotion - will rise in many middle-income countries. Already, today there are several examples of important pathogens resistant to multiple antibiotics.
For example, you've probably heard of MRSA, or methicillin resistant staph aureus, to give it its full name. It's the most common hospital superbug. Or Gonorrhoea, one of the clearest examples of a pathogen that has out-competed antibiotics.
Once treatable with sulphonamides (the original antibiotics), resistance rapidly emerged, followed by a form of penicillin resistance, which could initially be overcome by increasing the dose, but now penicillin doesn't work either.
There's also E coli, antibiotic resistant strains of Tuberculosis in humans, and more recently reported, colistin resistant gramme negative bacteria such as Klebsiella. As again, colistin was one of the last antibiotics available against this bacteria. If the covid pandemic has taught us anything it's surely the importance of not ignoring high consequence events that are heading our way, so why do we continue to ignore this global threat to our health?
The good, the bad and the ugly
Bacteria are everywhere and there are many different types. First, the harmless or even 'good' bacteria. Our intestines, for example, are home to many different commensal bacteria and they help keep our digestive system in good health. Then, we have the 'bad' bacteria, otherwise known as pathogens. These bacteria make us sick, for example, salmonella, tuberculosis, leptospirosis, pasteurella pneumonia, the list goes on.
And last, but not least, we have 'ugly', the antibiotic-resistant bacteria. These may or may not be pathogens, but here's the important bit: They have adapted to survive antibiotics. Whenever we use antibiotics, we impose a huge selection pressure, further speeding up the evolution of resistant bacteria.
But there's another crucial element to this: Bacteria can do something that animals can't, they can swap pieces of genetic material. Antibiotic resistance can be transferred to our worst pathogens. And this is how we get so-called antibiotic resistant 'superbugs'.
These are the disasters waiting to happen, which we must try and avoid; our worst pathogens, developing resistance to a multitude of antibiotics. A deadly cocktail, which can harm us all.
A story of dependency
The simple truth is that none of this will come as any surprise to microbiologists and we've been sleep-walking towards this situation for decades. AMR has been understood and acknowledged as an outcome since the very first discovery of sulphonamides in Germany in the late 1930s and many efforts have been made to control the use of antibiotics over the decades.
But since the 1940s a sort of antibiotic Gold Rush has not only changed the way medicine works, but also changed the way agriculture works across the developing world. Actively promoted by pharmaceutical companies during the 1960s, antibiotics are used in agriculture to combat pathogens in animals, to prevent new infections - and perhaps most importantly, to promote the growth of animals by improving feed efficacy.
Of course, this led to their adoption by progressive farming systems across the world and created a model of dependency. The figures speak for themselves. Intensive meat farming practices worldwide have, and continue to, play a large role in this problem:
Roughly three-quarters of all antibiotics sold each year are marketed for use in farm animals rather than humans. This is because for many years in the late 20th century, intensive farms relied on providing animals with continuous low doses of antibiotics, sometimes referred to as 'sub-therapeutic use' or growth promotion, a practice that is discouraged but continues today in many countries often under the guise of 'ensuring meat safety'.
Of course, as we know, this simply gives bacteria the perfect breeding ground to turn into pathogens. Antibiotics also are frequently accused of enabling poor conditions and overcrowding and leaving residuals that can trigger allergies in humans. But for the farmer they come with such significant benefits it's a habit which is proving difficult to kick.
And whilst there is an almost unanimous acknowledgement of the problems, changing farming practices is proving tricky.
The distribution of costs & benefit
Moreover, while antibiotics have enabled enhanced profitability in intensive systems with already tight margins; in poorer areas of the world, they have made rearing animals even possible.
As demand for animal protein rises globally, this is a problem which continues to disproportionately affect low- and middleincome countries, where pressure is highest to intensify farming systems and where populations yearn to consume more meat.
Therefore, reducing consumption requires some serious management. Consider the inherent difficulty caused by the distribution of the costs and benefits, where the cost of change appears mainly in the producing setting, and the benefits only appear to a large extent in the healthcare setting, the wider environment and society at large.
How did we get here?
But it's important not to demonise antibiotics. They're a valuable and an ancient medicine - traces of tetracycline (an antibiotic still in use today) were found in skeletons from ancient Nubians (350-550 AD) as well as in the guts of ancient mummies.
Modern medicine was revolutionised from the mid-20th century after Alexander Fleming made his amazing discovery of identifying penicillin, which was heralded as a miracle drug – as indeed it was and still is – and was heavily used in World War II to treat Allied troops, despite Fleming's warning that overuse could lead to mutant bacteria.
By the mid-1950s, Fleming's warning had become a selffulfilling prophecy as resistance to penicillin in humans had gradually built up due to the wide availability of the drug. However, it was the use of antibiotics in animals post-war that was the real game changer, when a British-American biologist Thomas Jukes discovered that in-feed use of tetracycline could help advance the growth of chickens.
In Europe, use of antibiotics for growth promotion has been banned since 2006, so why are we still seeing a rise in their use? The answer lies in some key policy failures.
In 1953, seduced by the thought of a post-war increase in meat production, the British government introduced the Therapeutic Substances (Prevention of Misuse) Act. Despite the Act's reassuring name, it legalised the inclusion of very low doses of penicillin in the feed of pigs and poultry, without the need for a veterinary prescription, for the purpose of growth promotion.
During the parliamentary debate, some concerns were raised about antibiotic resistance, but the then Health Minister, Iain McLeod MP, assured MP's that the government had received advice that 'there will be no adverse effect whatever upon human beings.'
Just one MP, Colonel Gomme-Duncan, spoke out strongly against growth promoters, asking: 'May I ask whether we have all gone mad to want to give penicillin to pigs to fatten them? Why not give them good food, as God meant them to have?'
Sure enough, by the late 1950s scientists were finding that strains of antibiotic-resistant salmonella were proliferating on British farms and their workers. The Swann Report effectively created a back door with far reaching consequences.
In 1969, responding to the emerging hazard to human health, the UK government commissioned the Swann Report which set out to end the overuse of antibiotics in farming and limit the spread of antibiotic resistance from animals to humans. It concluded that the use of antibiotics for growth promotion was a threat to human and animal health.
The Swann Committee proposed a solution whereby a distinction would be made between antibiotics that were acceptable for routine use in feed (such as macrolides) and those that should be reserved for human medicine (such as penicillin and tetracycline).
The recommendation of the Swann Committee was largely followed, both in the UK and in the European Economic Community. The use of penicillin and tetracycline as growth promotors was phased out. However, the Swann Report recommendation also created a back door: these drugs could still be used routinely for disease prevention in whole groups of animals with a veterinary prescription.
Whilst focussing on ending the use of medically important antibiotics for growth promotion, it made no proposals for ending other types of routine use, including preventative group treatments, because the short-term economic benefits to the industry were given priority.
Though hugely influential globally for its awareness raising it was a massive, missed opportunity. Swann essentially failed because, in trying to appease all parties, instead chose a compromise. Crucially, it recognised the important role that low concentration of antibiotics played in the growth rates of young pigs and poultry; a practice that has facilitated a prescription habit across much of the EU and certainly enabled commercial practice across the world to this day.
Finally, a 'Swann song' for routine and sub-therapeutic use?
In simple terms, opinion and guidance on the use of antibiotics still varies greatly from country-to-country. Sometimes presented as 'routine' use to prevent disease, the whole concept of prophylactic (preventative) treatment is widely debated. And it's clear that the term means different things to different groups. Many industry insiders argue that 'mass' or 'groupmedication' can often be necessary.
UK's Responsible Use of Medicines in Agriculture alliance (RUMA) say that preventative treatment is sometimes the best course of action. This is the idea of prophylaxis, in other words using antibiotics to prevent disease rather than using it to treat disease. Far from the way it can be portrayed, they argue, oral treatment of groups of animals through their feed (or mass-medication) can be the most effective treatment method.
This is especially so if given before disease affects their appetite. Catching and injecting individual animals can be also very stressful to the animal. Outdoor-reared animals, such as sows or free-range laying hens, drink rainwater, making application through the drinking water system unreliable and risks under-medication. Large groups of poultry could equally be stressed by catching, especially if a course involving daily treatment is needed.
Hence, this makes individual treatment impractical. In-feed medication may therefore provide the most practicable option in many cases. And, of course, it should be up to the vet and the farmer to decide the optimum way to administer medication, which remains under veterinary control or prescription in the UK and EU.
Moreover, during the last few years, RUMA says that the UK has seen a good reduction in use of antibiotics and improved susceptibility of e-coli to antibiotics. The UK VARSS (Veterinary Antibiotic Resistance and Sales Surveillance) Report published last month is certainly encouraging.
Overall sales of veterinary antibiotics for food producing animals decreased by 52% between 2014 to November 2021, while sales of highest priority critically important antibiotics for food producing animals reduced for the 6th consecutive year, representing only 0.5% of the total antibiotic sales.
For salmon, however, usage increased by 15.8 mg/kg since 2019,13.2 mg/kg (82%) higher than in 2017. But the UK or even the EU case is not the norm, and without a concerted and systemic effort from governments and farming policymakers worldwide we are not going to shake off the looming threat.
RUMA, and most British veterinary and farming organisations, do not support routine preventative use of antibiotics. But there is, however, a widely held and justifiable belief, by both medics and vets, that controlled intervention to prevent the outbreak and further spread of disease in infected or carrier animals, based on sound professional examination and advice, is better than cure.
RUMA draw a subtle but essential distinction; those antibiotics "must not be used to compensate for poor hygiene or for inadequate husbandry conditions or where improvements in animal husbandry could reduce the need for antibiotic treatment." John Fishwick, senior lecturer at the Royal Veterinary College (UK), emphasises why it's important to draw a clear distinction between therapeutic use and sub-therapeutic use.
'Therapeutic' use refers to the amount of a medicine required to successfully treat disease. However, around the world low, or sub-therapeutic, concentrations of antibiotics are still given as feed and water additives to suppress disease, improve daily weight gain and improve feed efficiency through alterations in digestion, which Mr Fishwick recognises, globally, is still a huge problem.
John Fishwick explains how in many countries, antibiotics are freely available and freely used. 'It's not my place to criticise [these countries], there are massive issues with antibiotic misuse, overuse and unregulated use all over the world. 'Human antibiotics are being used as animal growth promoters, and it's a major concern - it's very bad news and the sooner that stops, the better', he says.
"Antibiotics as growth promoters have no place in farming today.'However, Mr Fishwick concedes the while issues are acknowledged, solutions are complex. 'I wouldn't be so arrogant to say that countries are not behaving responsibly, but some have other issues to deal with, and they are really trying to get this sorted out. They are really struggling because people are poor, and they need these antibiotics to successfully rear the animals."
"But I think often people confuse that pretty terrible situation with what is actually quite a positive story in the UK where a huge amount of work has been done," he adds. "Using antibiotics as a growth promoter, thank goodness, is now illegal in the EU and I think it's recognised that it was an appalling practice," Mr Fishwick explains.
"Now, in the UK, we should very definitely only be using antibiotics to treat disease. We should not be saying, 'give this group of animals antibiotics at this stage because it's a high-risk period. That is absolutely considered irresponsible and extremely unusual, if not illegal.
And it's important not to demonise the role of antibiotics in farming systems, Mr Fishwick explains: 'One of the main ways this problem can be addressed is by careful stewardship of antibiotics in people and animals, and this requires joined up thinking.
'There's been a very unfortunate tendency for the animal health industry to say it's all down to doctors, and the medical side to say it's all down to animal husbandry and animal health, and in fact both sides of the equation need to be addressed,' he says.
A multi-pronged approach
Building awareness is the first step in addressing the public's behaviour and it seems there is much work to be done in that area. Research carried out by the Wellcome Trust to explore a consumer perspective on antimicrobial resistance, completed in 2015, revealed that the issue is still widely misunderstood by most people. ReAct is one of the first international independent networks to articulate the complex nature of antibiotic resistance and its drivers.
The team, which includes microbiologists, physicians, veterinarians and global health specialists are focussed on mobilising change at both a policy and grassroots level by sharing information across five continents. ReAct now has teams in Africa, Asia Pacific Latin America, Europe and North America. Andrea Caputo, MSc and PhD, says there's no one simple solution, that a multi-pronged approach is needed.
"There is no single 'silver bullet'; AMR is a systems failure requiring a cross-sectoral response," he says.
Outsiders and insiders
It is apparent that key to change will be outsiders, who see the problem and debate it in the media and lobby government to set targets: and industry insiders who see the problem and set about making practical changes to animal husbandry and farming practices. Mr Fishwick offers an analogy on this last point.
'Increases of antibiotic is often associated with poor husbandry. I often say this to my students - if we put you all in a dark classroom with all the windows closed, with the heating turned up, by the end day a lot of you are going to be quite unwell. "If we have people in lovely, uncrowded accommodation with lots of fresh air, they're probably going to come out all smiles. It's exactly the same with animals.
"There's a big drive in this country, and of course necessary all around the world, to improve husbandry, reduce stocking rates, look after animals well, house them and feed them well."
And when that doesn't happen, there's a tendency for people to cover-up the cracks with antibiotics, which obviously is very, very bad practice, both on a welfare front and an anti-microbial resistance front," Mr Fishwick adds.
Intensive farm systems across the globe have, without doubt, created a structural need for disease prevention, where the line between disease prevention and growth promotion remains blurred. Therefore, the whole issue surrounding antibiotics use raises important questions about our animal farming practices and expectations: What we are willing to pay for meat to sustain the husbandry required to keep animals healthy and equally, what we should be feeding animals.
We'll take a deeper look at these ideas – especially regarding functional feed additives like prebiotics, probiotics and phytobiotics, where huge investment is being made for poultry, swine and fish - available in the next edition of Milling and Grain.
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