Interesting article

Too much of a good thing

Antibiotics have transformed human health and saved millions of lives. Now, as a result of overuse, they are no longer working. The golden age of medicine has come to an end
 
Needwood House Farm is easy to miss. Only a small sign – the bright pink image of a pig – suspended from a fence post hints at anything of significance down the one-way track that leads off the main road. After a few hundred metres of bouncing over mud and gravel, it is the pungent smell that smacks you first. Then, the sound; the squealing, grunting and growls of 5,000 pigs crammed into this corner of rural Staffordshire.
 
A hundred or so piglets are excitedly clambering over each other or snuffling around the muddy floor of the gated outdoor enclosure where they are waiting to be transported for slaughter. Inside the great barns, 500 sows lie side-by-side in pens while their offspring fight for space at their teats.The air hangs heavy with ammonia, so thick it stings the lungs.
 
This is the flagship operation of Midland Pig Producers, which runs nine farms across the country producing 80 tonnes of meat a week to supply Tesco, Marks and Spencer, Waitrose and Asda. It is big. But only a few miles away over the border into Derbyshire, something even bigger is planned.

A decision is expected shortly on Midland Pig’s so-called Foston Mega Farm, which will house 25,000 intensively reared indoor pigs, making it one of the largest in Europe. The proposal has attracted huge opposition, with more than 20,000 letters from across the world. Pig welfare is, of course, an emotive issue. But campaigners insist that something greater is at stake here – something that the Chief Medical Officer has referred to as one of the greatest threats of the 21st century, alongside terrorism and climate change, and which this spring, is expected to be placed on the national risk register. Such farms rely on the use of antibiotics for sick animals, but as we rush to produce industrial quantities of ever cheaper food, we have sleepwalked into a human health crisis.

Antibiotics are no longer effective. The drugs that have transformed life and longevity and saved countless millions since penicillin was discovered by Sir Alexander Fleming in 1928 now saturate every corner of our environment. We stuff them into ourselves and our animals; we spray them on crops, dump them in rivers, and even – as emerged at a meeting of science ministers from the G8 last year – paint them on the hulls of boats to keep off barnacles.

As a result an invisible army of super-resistant bacteria has evolved, one that is increasingly claiming lives – currently more than 25,000 a year in Europe alone, around as many as die on the continent’s roads.

Many leading scientists and doctors and politicians are freely adopting the language of global catastrophe. Infections such as tuberculosis and septicaemia – the scourge of earlier centuries – are once again killing us at frightening rates. We have used, or are using, our so-called drugs of last resort. There is nothing left in the armoury and new drugs are not being developed. Welcome to the post-antibiotic age.

n 2012, at Needwood House Farm, a pneumonia outbreak swept through the herd. The piglets were taken off site and sows fed antibiotics with their food for six weeks. Those few that didn’t survive were incinerated. The outbreak – the first in eight years at the Farm – cost Midland Pig Producers £100,000.

“Antibiotics are expensive,” says owner James Leavesley. “The last thing we want to do as a business is use them. We don’t unless we have to. It’s done because an animal – just like a human – can fall ill. If we need to stop using them on farms, can we stop using them in hospitals as well, please?”

Pig Farming
At Needwood House Farm, Staffordshire, James Leavesley says antibiotics are only used as a last resort

Leavesley says intensive farming has come a long way since “barbaric” and “abhorrent” practices in the Sixties and Seventies. Nowadays, pens are better ventilated and excrement is sluiced away through grates.

“What we are proposing [at Foston] is going to be a cultural evolution. The whole point of the thing is to create an environment where we don’t need antibiotics.”

It is an admirable goal, but the reality is that modern British farms rely on antibiotics and on a vast scale. In 2012, some 409 tonnes of antibiotics were sold for animal use (a rise on the 346 tonnes sold the previous year), of which 85 per cent was for food-producing animals. The use of three classes of antibiotics classified by the World Health Organisation as “critically important in human medicine” has also increased. According to the latest Department for Environment Food and Rural Affairs (DEFRA) report, in 2012, 2.4 tonnes of fluroquinolone antibiotics were given to animals compared to 2.1 tonnes in 2011. Sales of the other “critically important” antibiotic classes – third and fourth generation cephalosporins (1.3 tonnes) and macrolides (40.9 tonnes) – also recorded small rises on the previous year.

“It’s getting worse, not better. It may be OK for five to 10 years but it’s not a sustainable model for the future. Otherwise we will lose our antibiotics.”

Zac Goldsmith MP

Veterinary medicine accounts for around 30 per cent of antibiotics use in this country, and yet, we are one of the better regulated in the world. An EU-wide ban on the use of antibiotics as growth promoters in livestock has been in place since 2006. In Britain, only vets can prescribe antibiotics for animals, although critics say this raises an obvious conflict of interest when they also sell them. Worldwide, the majority of the 100,000-200,000 tonnes of antibiotics manufactured every year is freely used in the agricultural, horticultural and veterinary sectors to keep animals healthy on industrial-scale farms. “It’s getting worse, not better,” says Zac Goldsmith, the Conservative MP for Richmond and treasurer of the newly-formed All Party Parliamentary Group on Antibiotic Resistance. “When you concentrate a very large number of animals, particularly pigs, in very cramped conditions, you are going to create all kinds of local and environmental problems.

“History tells us you can’t keep animals in those conditions without almost daily use of antibiotics. It may be OK for five to 10 years but it’s not a sustainable model for the future. Otherwise we will lose our antibiotics. There are all kinds of implications about mega farms. I know that the total use [of antibiotics] per head per animal has gone up 18 per cent in the past 10 years.”

Goldsmith talks with a quiet urgency from the corner of a tearoom in the Houses of Parliament. For a long time, he says, he has been one of the few outspoken voices from the backbenches on antibiotic resistance. But not any longer. There is growing concern at the highest levels of Government over the seriousness of the issue. The June meeting of the Parliamentary and Scientific Committee to discuss antibiotics was standing room only in the Commons committee room. Looking down from the wall was a portrait of Lord Palmerston (prime minister 1855 to 1858 and 1859 to 1865). Once more we are engaged in gunboat diplomacy, the rhetoric of war.

Last autumn, Britain launched its new Five Year Antimicrobial Resistance Strategy. Ministers accept the urgent need to reduce the use on farms, but it is not just in the food chain where resistant bacteria thrive in a generous swill of antibiotics. According to Chief Medical Officer, Professor Dame Sally Davies, GPs in England currently prescribe 35 million courses of antibiotics a year. As patients we demand them, putting huge pressure on doctors to prescribe pills for viral infections such as a sore throat for which they are useless. Too many GPs who should know better acquiesce.

Dame Sally and other experts say it is a practice we must stop now. “I care about my children and grandchildren, let alone my own old age,” she says. “If we don’t sort this out, not just as a nation, but globally, we risk going back to a time where people die young.

“We risk going into a post-antibiotic era, and that could start any time in the next 10 or 20 years, when modern medicine becomes impossible. Routine surgical procedures – hip replacements, caesarean sections, modern cancer treatments – all are based on using antibiotics to prevent or treat infections. Without them, people will die.

“Before antibiotics, 43 per cent of people died of infection in this country. At the moment it is seven per cent. I predict without proper conservation and new antibiotics, our death rate will steadily creep up. We risk returning to a situation like that. And the stupidity is, we don’t have to.”

o truly understand the extent of the problem, one must look beyond Britain’s borders. Compared to other countries, in particular the emerging powerhouses of India and China, we are well ahead in reducing use of antibiotics. But there is only so much we can do alone.

This frustration was evident at the first evidence session of an ongoing parliamentary inquiry into antimicrobial resistance at Portcullis House which started in December. As Sharon Peacock, professor of clinical microbiology at the University of Cambridge told MPs: “Much of the resistance we see in this country is actually potentially imported from other places. We have to recognise that and understand what is happening in the bigger picture.”

Ours is a globalised world, and 70 per cent of the bacteria in it have now developed a resistance to antibiotics – including those drugs regarded as our last line of defence. Superbugs spawned in a Chinese hospital or a polluted Pakistani river cross continents quicker than we can discover them. One recent study of 100 Swedish travellers visiting countries outside of Northern Europe found one in four young men had antibiotic resistant bacteria present in their guts on their return.

HOW RESISTANCE BREEDS

 

We carry resistant microbes wherever we go. In 2011, there were almost 35,000 cases of multi-drug resistant tuberculosis recorded in Europe – a six-fold increase in as many years. London is now known as the TB capital of the western world. During the past year around 3,500 residents were diagnosed with the disease (out of around 9,000 across the UK) with boroughs like Newham and Ealing experiencing rates of infection comparable with the developing world.Treatment of multi-drug resistant TB is vastly expensive, costing between £50,000 to £100,000 per patient over two years, and putting a huge strain on hospitals and budgets.

Necessity negates political correctness. Only last month, Professor Ajit Lalvani, from the National Heart and Lung Institute, called for more screening tests to identify latent symptoms of TB that could be brought into the country by immigrants. For it is from distant shores where much of this bacteria comes from.

About 75 per cent of the cases nationwide occur among people born in countries where TB is more common, mostly South Asia (60 per cent of cases) and sub-Saharan Africa (22 per cent). Multi-drug resistant cases are also increasing in Eastern Europe. The complicated therapies required to treat the disease are more difficult to impose over language barriers and with vulnerable patients, resulting in unfinished courses of antibiotics; another major factor that increases resistance.

TB is by no means the only disease of concern. In November, the EU’s disease monitoring agency warned that Europe now faces a growing threat from bacteria that are resistant to the last-resort class of antibiotics known as carbapenems, with almost all European countries now having reported cases. The data from the European Centre for Diseases Prevention and Control showed that the proportion of bloodstream infections due to Klebsiella pneumoniae, a common cause of illness in hospital patients, that were resistant to carbapenems was now above five percent in 2012 in five countries – Greece, Cyprus, Italy, Romania and Slovakia. In 2009, only Greece and Cyprus exceeded that threshold.

Even some of those sent out to protect us are bringing back killer diseases from abroad. Multi-drug resistant gram-negative bacteria have been recorded in British and American soldiers returning from Iraq and Afghanistan. Bacteria fall into two categories: gram-negative and gram-positive. Gram-negative bacteria possess thin cell walls (5 to 10 nanometres) adept at flushing out antibiotics, making them much harder to treat. Gram-positive, which include methicillin-resistant staphylococcus aureus – better known as hospital superbug MRSA – have thick cell walls (20-80 nanometres) that better retain antibiotics.

So many infections of gram-negative Acinetobacter, which causes a variety of diseases ranging from pneumonia to serious blood or wound infections, were recorded in troops in Iraq, that the disease was nicknamed “Iraqibacter”. Pathogens would also blow into soldiers’ wounds in the dust and dirt of Helmand Province in Afghanistan, causing a variety of diseases ranging from pneumonia to serious blood or wound infections. The number of cases fuelled claims that insurgents were lining IEDs with excrement or rotting animals.

And then, there are the medical tourists. Those who visit hospitals in Asia for cheap cosmetic surgery or other operations to avoid waiting lists are another main driver of the problem. In 2015, it is predicted 3.2 million people will travel to India for surgery. Here antibiotics are freely available for sale over the counter (at least until later this year when new laws come into place). “I think things have got progressively worse in Southern Asia, largely because of the medical tourism industry,” says Professor Tim Walsh, a microbiologist at Cardiff University. “If you look at the Calcutta Times, on the front page is a huge advertisement for cosmetic operations. People come from all over the world.”

“It’s almost like the perfect storm. It’s going to be very difficult for us to win this battle. In fact, I would say it’s impossible.”

Professor Tim Walsh

Walsh was part of the team that discovered NDM-1, an enzyme that confers resistance on a range of bacteria. In short, it makes already dangerous bacteria such as E.coli and cholera, far worse. The ND stands for New Delhi, where it was discovered in 2008. In the ensuing years it has claimed lives and spread panic far beyond the subcontinent. Walsh is currently assisting the UK government with estimates on the extent of antibiotic resistance by 2030-2050 and at the same time overseeing the world’s largest clinical trial in Pakistan and India looking at multi-drug infection in extreme drug resistant bacteria. The data, he says, “is quite frightening”.

“Bacteria are able to adapt, mutate, their DNA is very fluid. This is all happening in real time. We are up against a foe and it is a scenario combined with antibiotic industries around the world pumping out drugs and polluting environments, as well as overuse in our communities. Lots of countries have no idea at all about resistance rates.

“It’s almost like the perfect storm. Putting all that information together I would say it’s going to be very difficult for us to win this battle. In fact, I would say it’s impossible. Certainly it is going about it the way we are at the moment.”

One British man who, unlike the medical tourists, ended up in an Indian hospital against his will is freelance journalist Russell Cronin. In April 2011, during a meditation trip to Bihar, in northeastern India, the 49-year-old Londoner was electrocuted by a faulty shower at his hotel. He suffered horrific burns, which eventually resulted in him having his left hand amputated. After being treated at two Indian hospitals, the hotelier agreed to pay for a flight home to England, if Cronin wrote a note exonerating him from further liability. When he landed he was rushed from the plane to Bristol’s Frenchay Hospital where it was discovered, aside from the devastating injuries, that he had contracted five multi-drug resistant gram-negative bacteria carrying the NDM-1 enzyme, including a super immune strain of cholera.

“I was in a really bad way,” he says. “I didn’t know about the bugs until I came round and found myself in the isolation unit. They told me what it was but I had no idea what it all meant. I was still in a state of shock to discover that my hand had gone.”

Russell Cronin was hospitalised in India and nearly died after contracting a host of multi-drug resistant bacteria.

Cronin was eventually discharged after 11 weeks in hospital. He was treated with colistin, an antibiotic so toxic it was discarded in the 1960s but has now been dug out again in desperation. Renal toxicity is the most common adverse effect of colistin treatment, none the less it may well have saved his life. “The doctors have told me how close I came to dying,” he says.

Hospitals are increasingly being confronted with cases such as Mr Cronin, with antimicrobial resistance now costing the economy an estimated £10 billion a year. But those within the medical profession say students exhibit a staggering lack of knowledge about the issues we face. “One of the major problems we find is the lack of microbiology training that junior students have,” one consultant microbiologist says. “It is just two hours, in that time you can’t do anything. And it is now a very common practice in hospitals to use antibiotics of last resort. It’s very widespread and I have seen a lot of drug-resistant bacteria.”

In November, a Europe-wide study of final year medical students tested knowledge of antibiotic prescribing and resistance. Laura Piddock, professor of microbiology and deputy director at the institute of microbiology at the University of Birmingham and director of Antibiotic Action, describes the results as “lamentable”. “It’s not the fault of the students or the medical schools. The problem is the curriculum. What it means is we don’t get the time we would like to teach this area properly.”

ithout new drugs, there is no hope. Between 1935 and 1968, 14 different classes of antibiotic were developed. In the 45 years since then, only five have been brought out. No new classes have now been developed since 1987. The problem, is profit potential and profit depends on volume. Many pharmaceutical companies have pulled out of development altogether, focusing attention instead on drugs for chronic conditions, such as diabetes or blood pressure which patients have to take for years, rather than courses lasting just days or weeks. Professor Anthony Kessel, director of Public Health Strategy at Public Health England, says it is time to engage in a “moral debate” over the lack of new drugs, and admits rationing could now be on the horizon.

“We may get to a situation where we have to think about rationing antibiotics. We are not there yet but if we really run out you can imagine that as a possibility. You can imagine a situation in the future where we have to develop a new antibiotic but not make it available straight away and keep it for emergencies. These are the type of solutions that we haven’t really talked about in great depth yet, but are possibilities.”

Some governments are now so concerned they are taking an active role in research. In a large glass and chrome facility near a small town called Collegeville, 30 miles northwest of Philadelphia, scientists are working to discover new antibiotics that can save the world. Since 2009, some 30 scientists and technicians have been based here in a GlaxoSmithKline “discovery performance unit”. Last year, the company was awarded up to $200 million by the U.S. government to develop new drugs to counter antibiotic resistance and bioterrorism – in particular, in case of anthrax attack. David Payne, head of the unit, says there are three possible molecules currently being tested, although admits the scale of the challenge is immense. “You’re working in very unknown territory because nobody has ever done it before.”

“A lot of companies have withdrawn from developing antibiotics. Only very few are doing it now”

David Payne

Payne says the difficulty is three-fold: poor profit potential; difficult science (the easier discoveries have already been made); and working around complex regulations, although he says the latter problem is now changing. According to a Chatham House report published last October, in 2004, only 1.6 per cent of drugs in development at the world’s 15 largest drug companies were antibiotics. GlaxoSmithKline is now just one of four major pharmaceutical companies left working on antibiotics.

“A lot of companies have withdrawn from this area,” Payne says. “If you go back 10 years just about every big pharmaceutical company you were aware of would have had a pretty large antibacterial discovery group. Only very few are doing that now.”

It may seem a bit rich for the global pharmaceutical industry to complain about profits when, this year, its value is expected to reach £550 billion. Yet it can cost, we are told, hundreds of millions of pounds to bring a new single drug to market. The profit imperative ensures that the drugs chosen for research are those most likely to provide high returns, while far more gets spent on marketing products than developing new ones. According to an analysis of drug company spending published in the British Medical Journal in 2012, for every £1 spent on basic research, £19 is spent on marketing.

The result is a yawning void, one that has prompted the Association of the British Pharmaceutical Industry, among others, to call for a comprehensive review of the research and development environment. The UK government’s new five-year strategy to tackle resistance does address this in part; some £4 million being allocated for a new research unit on antimicrobial resistance to be established by the National Institute for Health Research from this April. There are also plans to encourage greater public-private investment in discovery and development and promote more streamlined research and collaboration within the industry.

here is a growing political will to address a complacency that set in as far back as the 1970s and even now – without new drugs in the pipeline – better infection control has been proven to make an immediate impact on winning the fight against resistant bacteria. Health professionals point to plummeting MRSA death rates in Britain, which have fallen by around 80 per cent since 2008. Improving public awareness is also key. Around half of people in the UK still do not know that antibiotics are inappropriate to treat colds, flu and viruses, according to evidence given a few weeks ago to the Commons Science and Technology Committee.

But it may yet still all prove to be too little, too late. Sir Alexander Fleming did warn us. During a speech in Stockholm in 1945 after accepting his Nobel Prize, Fleming sounded “one note of warning” over bacteria becoming resistant through inappropriate use of the drug. “The time may come when penicillin can be bought by anyone in the shops.’’ he said. The idea of his precious discovery being stockpiled by online pharmacies, used to fatten up our fish and livestock, dumped in rivers and sprayed over fields, would have baffled and horrified him in equal measure.

The laboratory where Sir Alexander Fleming discovered penicillin is kept preserved at St Mary’s Hospital.

At St Mary’s Hospital in London a plaque marks Fleming’s discovery in September 1928 “to the glory of God and immeasurable benefit to mankind”. His laboratory is perfectly preserved. His old Beck’s microscope sits on the wooden desk amid dusty glass bottles, books and test tubes. Fleming’s bacterial samples were deemed so vital to the future of mankind, contingency plans were drawn up in case of Nazi invasion during World War Two for them to be smuggled out of the country in the lining of his suit.

Today at St Mary’s – as in every other British hospital – that wonderful armoury, in which Fleming laid the first weapon, has been picked bare while the enemy has evolved. As Professor Jeremy Farrar, director of the Wellcome Trust, said in an interview last month, “We have been through a golden age and we have become complacent. We’re watching evolution happen. This will come up steadily over years and it has already started. It’s been happening for the last decade or more and will continue. It will creep up on us almost without noticing. This is getting to the tipping point where you and your families will start to see this.”

We are sleepwalking back into a time where something as simple as a grazed knee or a scratch acquired in the garden will start to claim lives. The golden age of medicine is behind us.

Author: Joe Shute
Editors: Liz Hunt, Joel Gunter
Designers: Mark Oliver, Scott Jones
Developer: Dan Palmer
Title image: Alamy
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