Friday, January 15, 2016

MCR-1: Tragedy of the Commons for Antibiotics

CAFO factory farms have done it again.  MCR-1 may be the clarion call to the end of the antibiotic era, where most bacteria will be totally resistant to all or most antibiotics.

Originating on a Chinese CAFO  (Concentrated Animal Feeding Operations) factory farm for pigs, scientists discovered the plasmid-mediated colistin resistance mechanism ("MCR-1" #mcr1) that gives bacteria resistance to an extremely important antibiotic called colistin. 

I call it another example of #TragedyOfTheCommons, this time attacking the "Antibiotic Commons".

CBC Radio program The Current has summarized the MCR-1 issues quite nicely in a 25 minute segment.  Listen here.

Colistin resistance has been found encoded within a bacteria's plasmid, a piece of genetic material found in most cells, including bacteria.  Plasmids can be rapidly transferred between different bacteria, makings rapid spread of this antibiotic resistance highly likely.  That newly discovered colistin resistant plasmid is called "MCR-1"

Nothing New Under The Sun

Jim Romahn of Agri007 informs me this risk from MCR-1 is nothing new.  Transference of antimicrobial resistance via plasmids was a known risk back in 1969 when Lord Swann presented his "Report of the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, 1969"  to the UK Parliament.

The 1969 Swann Report said:
"the administration of antibiotics to farm livestock, particularly at sub-therapeutic levels, poses certain hazards to human and animal health"; in particular it had led to resistance in enteric bacteria of animal origin. This resistance was transmissible to other bacteria (it had been the discovery that this might be so, followed by an epidemic of resistant S. typhimurium in 1963-65, which prompted Ministers to appoint the Committee); and enteric bacteria were transferable from animals to man. 
It therefore recommended that only antibiotics which "have little or no application as therapeutic agents in man or animals and will not impair the efficacy of a prescribed therapeutic drug or drugs through the development of resistant strains of organisms" should be usable for growth promotion. The Report named the following antibiotics, which were then in use for growth promotion, as unsuitable for such use: chlortetracycline, oxytetracycline, penicillin, tylosin (a macrolide related to erythromycin) and the sulphonamides. The Government largely accepted these recommendations.
The Report recommended that a single advisory committee, constituted under the Medicines Act 1968, "should have overall responsibility for the whole field of use of antibiotics and related substances whether in man, animals, food preservation, or for other purposes". It also recommended research into alternative means of growth promotion; and improved surveillance and epidemiology of diseases common to animals and man.

Government:  Hare or Tortoise

Now we don't want to rush the governments of the world, but we have been on this Mis-Use of Antibiotics for the last 46 years

Isn't it about time that we can move forward with confidence and clarity about antimicrobial mis-use?

China Syndrome

Medscape reports:
  • China is the world's largest producer of both pork and chicken;
  • About 10% of China's pork and chicken is exported to other countries;
  • 22.3% of China's retail pork samples, and 28% of chicken meat samples were infected with MCR-1 as of 2014;
  • 1% of inpatients in China's health care system with infections have MCR-1 as of 2014
That doesn't mean the world can be saved by slapping a ban on all things Chinese, and impose travel restrictions.  It's already too late.

MCR-1 Contamination of the Planet

Today, 23 countries have found MCR-1 present, dating back as far as 2005. Canadian scientists have found MCR-1 in samples taken from an Ottawa hospital patient who had previously traveled to Egypt, as well as ground beef sold at Canadian retail stores as early as 2010.  France found MCR-1 in samples taken from ill veal calves way back in 2005.

The bugs know what they're doing.  Us stupid humans might eventually find out what the bugs know and what the bugs have been doing all along, however that human knowledge will often be gained 10 years too late.  Is this reason enough for the Precautionary Principle to become irrefutable public policy?

As far as we know today, MCR-1 bacteria are not resistant to other antibiotics, but that can soon change. See the previous paragraph.

Colistin:   The Ancient Wonderdrug is Re-born

The colistin drug was discovered in 1949, with its use on human infections starting in 1959.  Colistin was found to be toxic to the kidneys and nerves of humans, so ongoing use of colistin was dramatically reduced, thereafter limited to just drastic situations for very sick humans. In North America, colistin has been reserved as a "antibiotic of last resort" due to its powerful effects on infections, as well as the significant negative side effects for humans.  That meant minimal sales income for the Big Pharma manufacturers of colistin

Did someone bother to tell China about this decision on colistin?  Maybe China didn't get the Memo.

Tough Questions for China, Big Ag., & Big Pharma

I have some questions about China and colistin:
  1. Who is using colistin in China? 
  2. Is it just the Chinese Big Ag. CAFO factory farms that use colistin?
  3. Have any Small Flock farms used colistin?
  4. Whether CAFO or Small Flock, who taught the Chinese about colistin?
  5. Did the Chinese government suggest or force some or all farms to use colistin?
  6. Were North American, European, or other "experts" (with or without self interest, conflict of interest, or bias) responsible for training, selling, or suggesting the use of colistin?
  7. If foreigners aided or abetted the Chinese starting to use colistin, do these outsiders have some stewardship, liability, or responsibility for the imminent disaster from the use or mis-use of colistin?
  8. Did the use of colistin take off in China because foreign "Snake Oil Salesmen" were preying on dirt poor, peasant farmers in China? 

I don't know the answers to these interesting questions.  If you do know for sure, please post the answers below (and the source of your knowledge) so we will all know.  I sense that China is all grown up and can stand on its own two feet, both now and 10 years ago when colistin use in China was just starting.  However, I also assume that there is significant variation from the most aware, to the least aware person in China.   

Look at how many Canadians fall each year for the ongoing Nigerian scams, phishing, and other frauds. Was it the same in China for colistin?  Some media reports say that colistin is used for the large Chinese CAFO farms, so that is what we will assume is true until we have better knowledge.

My Assumptions

I assume that:
  1. Chinese CAFO's are as bad or worse than North American CAFO's
  2. China realized that they needed a strong and effective antibiotic for their CAFO factory farms for chicken and pork;
  3. China couldn't or wouldn't afford the expensive, modern drugs and antibiotics that have been used in North American CAFO factory farms for the last 65 years.
  4. The patent on colistin had run out, and this drug technology was free for the taking.
  5. China learned that farm animals could be treated with colistin, survive the terrible CAFO experience, and avoid most side effects that limited colistin use by humans.
  6. China learned how to manufacture colistin for the rapidly growing number of Chinese CAFO farms.

China:  Their Colistin Production & Use

The Guardian reports that China is now one of the world’s largest users and producers of colistin for agriculture and veterinary use. Worldwide, the demand for colistin in agriculture is expected to reach almost 12,000 tonnes a year by the end of 2015, rising to 16,500 tonnes by 2021.

National Geographic reports:   "Of the top ten largest producers of colistin for veterinary use, one is Indian, one is Danish, and eight are Chinese.  Asia (including China) makes up 73·1% of colistin production with 28·7% for export including to Europe."

One Chinese manufacturer chosen at random, boasts that they can  supply 1000 kg per day of colistin.  It is unknown if this is the plant's maximum capacity, or just the un-sold capacity for which they seek additional customers.  They recommend colistin use for calves, lambs, chicken, turkey, and rabbits.

A search of Alibaba shows 85 pages of ads from  Chinese colistin manufacturers, with about 38 ads per page, for an approximate total of 3,230 ads that sell the colistin antibiotic for agricultural use.  Some of these ads may be duplicates, or slight variations on the same product (eg. different packaging).  Even so, that's a lot of ads and commercial activity focused on just one agricultural antibiotic.

Colistin has been used for more than a decade in huge quantities in the Third World (especially China) as a tool to artificially increase farm profits. Colistin is mainly used for treating intestinal infections (or CAFO living conditions) for rabbits, pigs, poultry, veal calves, cattle, sheep, goats, and aquaculture (ie. fish farms); including animals producing eggs and milk destined for human consumption.  The primary uses for colistin are pigs and chickens.  Colistin is also used to treat horses with infections.

CAFO-based Use of Antibiotics

Whether in China or elsewhere, factory farmers increase their profits by feeding their animals the colistin drug (and other witch's brew) on a chronic basis. Colistin can help ensure higher profits and lower risk for the farm by lowering the farmer's risk of an animal becoming sick or dying, and helping the animal gain weight faster.

Animal absorption of orally dosed colistin (ie. colistin added to the animal's food and/or water) is very poor, meaning most of the drug never leaves the animal's digestive tract, requiring large doses of the drug to get the necessary effect.  This means the manure and other farm waste streams will have a high concentration of colistin, and that drug will tend to travel off-farm to the surrounding environment (ie. via manure spreaders, wind, and water flows).  What happens for the Chinese village that takes its potable drinking water from a stream just downstream of a CAFO farm that uses colistin?

Antibiotic Priority:   Human or Animal?

On a kg. per year basis, about 80% of all antibiotics in the world are used on farms to treat animals, and 20% are used to treat humans.  While the drug sale price for agricultural use is much lower than human drugs, they make it up on volume.

In 2013, Pfizer (the world's largest pharmaceuticals company), spun-off its 80.2% interest in Zoetis (the world's largest agricultural drug company), for a sale price of $10.3 Billion.  That makes Zoetis worth  $12.84 Billion.  In 2014, Pfizer's gross sales from continuing operations was $9.1 Billion; just 70.9% of the value of Zoetis. 

I therefore suggest that the agricultural side of Big Pharma is just as important as the human side, if not bigger.

Because colistin wasn't being used much for humans,  there was little or no antibacterial resistance developing from this limited use, in spite of colistin having been around for 66 years.  Meanwhile, other "drugs of last resort" were developing antibiotic resistance (eg. carbapenem resistance in Gram-negative bacteria was reported in 2012, and was quickly seen as an extreme concern, as few therapeutic alternatives remained for humans).  This growing resistance rendered these "drugs of last resort" less useful, or useless to help people.  As drug resistance grew for carbapenem and other drugs, colistin started to be used more and more to treat human infections.

When you use a drug on a handful of very sick people as a "drug of last resort" used by medical professionals, the risk of developing antibiotic resistance is pretty small.

What about feeding that same drug to millions of farm animals?  I suggest the risk of developing drug resistance from CAFO agricultural operations is orders of magnitude bigger.

As you can guess, these two simultaneous but different uses of colistin would soon collide.  The dramatic collision between the conflicting uses of colistin occurred when MCR-1 was born.   Chinese researchers found colistin resistant bacteria, and that resistance was readily transferred to previously non-resistant bacteria while the scientists watched.  Further investigations showed the resistance to colistin had been transferred by a special plasmid that had never been seen before; an MCR-1.

Rather than hiding it, the Chinese scientist alerted the authorities, and the Chinese government allowed the publication of this critical info in the Lancet, the leading medical journal.

Well done China, for quick & full disclosure.  This is proof positive that the Chinese are team players in the world community.

I find it interesting that we usually get delay, deny, destroy, defend, distract, deride, and deflect from Canada's Chicken Mafia.  Thank God MCR-1 occurred in a Chinese CAFO, rather than Canada.

MCR-1 Impact on People

MCR-1 will primarily effect people with immune compromised systems.  Unfortunately, about 30% of Canada's population fit that category.  While you may not have a compromised immune system, it is likely that you are surrounded by people who are immune-compromised.  Once an immune-compromised person becomes infected, with life threatening consequences, you may be next as their growing infection might spill over to you via direct or indirect contact with those immune-suppressed persons who get hit by MCR-1.

While the human use of colistin has been previously limited, not so around the world.  China and other developing nations have been using huge amounts of collistin on farm animals (eg. pigs, chickens, etc,).

Antibiotic Mis-Use:   Who to Blame?

Why would Chinese farmers do this colistin treatment to their animals? 

Chinese farmers treat their pigs, chickens, and possibly other animals with colistin because:
  • Chinese farmers can buy colistin at a cheap price;
  • There are significant, immediate benefits to the farmer's pocketbook;
  • There are no laws against it; and
  • Colistin has acceptable side effects on animals (significantly less than those on humans).
Those colistin treated farm animals eventually become food for the Chinese people, as well as food exported to the rest of the world.

Unfortunately, Chinese farmers chose to increase their personal, private profits, while the risk and costs from the farmer's questionable behaviours get pushed onto the unsuspecting public.  It isn't just Chinese farmers; Canadian and USA farmers are just as guilty, European farmers less so recently, but all of these still do it to a lesser degree.  For example, Canadian poultry farmers and egg hatcheries have been guilty of abusing ciprofloxin, ceftiofur, and other Class I antibiotics.

Do you know where the food in your grocery store comes from and how it was raised?  Again, you can only truly know your food by knowing your local farmer, coupled with traceability and full disclosure.

It isn't just farmers who are guilty of antibiotic mis-use.  Humans who are non-complaint during the taking and/or disposing of their antibiotics are also guilty.

In other words, there is enough blame to go around for everybody.

Tools to Help Solve Antibiotic Mis-Use

When a problem is large, important, urgent, complicated, and diffuse, Pareto says we should focus our efforts using the 80/20 Rule.  More than 80% of all antibiotics are used in agriculture, exactly fitting the 80/20 Pareto Rule.  In addition, most of the worst violations (based on magnitude, frequency, incidence rate, prevalence rate, severity, risk, and detectability) all occur in agriculture.

Therefore all of our efforts to find and enforce a solution should be focused in agriculture.

These cases of on-farm antibiotic mis-use usually happen at CAFO's, also known as factory farms.  Therefore we should put all of our attention and resources against mis-use of antibiotics on CAFO farms.

As a small flock farmer, I have never used antibiotics for growth promotion.  I suggest it is the rare (I doubt any) small flock poultry farmer who would use antibiotics for growth promotion. I find no need to use ionophores (a non-antibiotic) to control coccidiosis.

In contrast to small flock farms, CAFO poultry factories would have thousands of dead birds without using their coccideostats and antibiotics.  Agricultural experts who work for the Ontario government have stated that it is impossible to raise commercial chickens without the use of antibiotics.  If a CAFO chicken factory stopped using antibiotics, and repeatedly suffered huge mortality rates, soon the CAFO chicken factories would die a different death:   bankruptcy

Therefore, we need to focus our antimicrobial efforts on CAFO factory farms.  After the CAFO-based mis-use of all antibiotics (and related products) is solved, we can move on to the secondary priorities.

The fight against CAFO-based mis-use of antimicrobials should receive first pick of all available government resources and attention (eg. manpower, research, $, media releases, surveys, audits, regulatory action, etc.) until the battle is won.  No secondary efforts (eg. hospital use of antibiotics, non-CAFO use, etc.) or other distractions should be allowed to occur if they would impede or distract from CAFO-based antibiotic mis-use.  These seemingly radical recommendations are based on Pareto, and Project Management principles (PMBOK and CCPM); all of which are well established methods to get the greatest impact as quickly and cheaply as possible.

Canada's Plan Against Antibiotic Mis-Use

The Canadian Federal Government has developed a framework to attack antimicrobial resistance, which has a focus on Surveillance, Stewardship, and Innovation.  Sounds nice, doesn't it.   Unfortunately, after reading what that means, it seems to me that Big Pharma and Big Ag. lobbyists were involved in the drafting of that framework, achieved regulatory capture, and controlled the development of that Federal Government plan through delay, denial, distraction, defending, destroying, deriding, and deflecting.  Apparently, they never heard of Pareto, and the previous Conservative Government didn't want to rock the boat for their friends in the Big Pharma-Big Ag. industries.

A Sham:   Canada's Ban of Antibiotic Growth Promotion

A Canadian ban is scheduled to come into effect in 2017 on the use of antibiotics for animal growth promotion, similar to what is planned in the USA.  It used to be that some antibiotics caused some animals grow more quickly and reduced their mortality rates (ie. think Frankenstein, coming back to life, and unable to be killed).  Note that this doesn't necessarily mean that the resulting antibiotic-enhanced meat is nutritionally better or safer; likely the contrary is true.   Today, antibiotics are fed to farm animals with little or no proof that they are effective for the intended purpose; especially in real farm conditions.  The ideal laboratory conditions that Big Pharma may have based their drug research upon may not apply to the real CAFO farm conditions.  Colistin is so old, there is little research ever done on efficacy or risk.

Most antimicrobial drugs can be used as growth promotants, or to treat a disease.  Only "growth promotant" use will be banned in 2017.  When the 2017 growth promotant ban comes into effect, will Big Ag. force or influence their Veterinarians to write prescriptions for the continued use of their antibiotic drugs of choice, as permitted in the pending regulations by a mile-wide loophole in the 2017 ban?

One of the biggest problems in CAFO farms is that Big Pharma aids, abets, and encourages these antibiotic mis-uses.

Un-Holy Alliance between Big. Ag. & Big Pharma

In general, Big Pharma may have some ancient dusty, limited research to indicate some positive effect for an agricultural drug, perhaps decades previously. Are these Big Pharma studies on antibiotic use on farms similar to the ones conducted by &/or for the tobacco industry that showed smoking didn't cause cancer, was not addictive, and was good for you?  Do those ancient results still apply to today's CAFO farms in all cases?  It's possible that the antibiotics being used have no noticeable effect (or are a detriment), yet they are still used today based on that antiquated Voodoo quasi-research by biased researchers.  If true, that un-necessary use of antibiotics that are wrongly encouraged by that faulty research brings no benefits, but it also brings the guaranteed risk and costs of antimicrobial resistance from this pseudo science; based upon a Big Pharma--Big Ag. unholy alliance.

In Canada, the farmer really doesn't care about the cost of  the drugs he feeds the animals, as he receives guaranteed reimbursement for all standard costs, plus a handsome profit margin.  All costs are fully passed on to consumers.  If farmers had to justify the spending of their hard earned money on questionable drugs each month, they might ask Big Pharma some tougher questions.  If the Supply Management industry spends huge efforts to justifying the use of CAFO antibiotics, they might find these potent and risky drugs aren't totally necessary, they stop buying, their farm costs go down, and the next cheque they receive under Supply Management for their farm gate price goes down accordingly, and their farm markup also goes down as it's based on a percentage of the costs, and the CAFO-based Supply Management farmers then earn less money.  Do you see one reason we have an unholy alliance between Supply Management (Big Ag.) and Big Pharma?

When Big Pharma's conducts R&D for an antibiotic, huge amounts of money are spent.  Big Pharma wants to recoup that investment any way they can, as quickly as possible.  Big Pharma is highly motivated to get cash flow NOW to recoup their R&D expenses.  While they may be limited within the developed world to "do what's right" by government regulators and the fear of lawsuits or fines when they get caught, those same forces don't exist in the undeveloped world.  Unfortunately, Big Pharma isn't internally restraining themselves to "do what's right" in the Third World.  The big cost is the R&D, while the cost to manufacture the drug is dirt cheap.  Does Big Pharma decide on a Third World price for their antibiotic so that Third World agriculture can be enticed to use it, thereby generating instant cash flow for Big Pharma, regardless the long term consequences for the entire world?

Bad science and unethical use of antibiotics anywhere in the world will eventually result in the growth and spread of these antimicrobial apocalypses indirectly, as seen by MCR-1.

Antibiotic Resistance:  MCR-1 and Beyond

MND-1 (a.k.a. NDM-1), is another example of antibiotic resistance, and the consequences for mankind.  Medical News Today says:
"NDM-1, which stands for New Delhi metallo-beta-lactamase-1 is a gene (DNA code) carried by some bacteria. If a bacteria strain carries the NDM-1 gene it is resistant to nearly all antibiotics, including carbapenem antibiotics - also known as antibiotics of last resort.

Carbepenems are the most powerful antibiotics, used as a last resort for many bacterial infections, such as E. coli and Klebsiella. The NDM-1 gene makes the bacterium produce an enzyme which neutralizes the activity of carbepenem antibiotics.

A bacterium carrying the NDM-1 gene is the most powerful superbug around.
As of 2010, some strains of bacteria, such as E. coli and Klebsiella pneumoniae carry the NDM-1 gene.  NDM-1 has spread from India, to Europe, Australia, and is now in Canada and USA.
Today, CDC estimates 2.3 million people per year in the USA will get sick this year from an antibiotic resistant infection, and 37,000 will die as a direct and indirect result of antibiotic resistance.

Health Canada reports a 14-fold increase in the use of last-line antibiotics to treat difficult infections since 2002, and more than 18,000 patients acquire multi-drug-resistant strains of bacteria each year in Canada.  Canada doesn't collect antibiotic resistance statistics similar to CDC, but based on 10:1 population ratios between US and Canada, we can estimate that 230,000 Canadians become sick, and 3,700 Canadians die each year from antibiotic resistance.

This Blog has also been pointing out the antibiotic crimes and misdemeanors in the poultry industry and in farming in general (see here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here).

World Health Organization ("WHO") reports that in 2013, there were about 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB). Extensively drug-resistant tuberculosis (XDR-TB, ie resistant to all known drugs) has been identified in 100 countries.  MDR-TB requires treatment courses that are much longer and less effective than those for non-resistant TB.  USA's Centre for Disease Control ("CDC") offers similar warnings.  XDR-TB can no longer be effectively treated by antibiotics for 50% to 70% of patients.  This antibiotic resistance was primarily started by the mis-use of TB antibiotics, primarily in the 3rd world.

The use of antibiotics in agriculture is primarily an enteric (gut or digestive) system focus, not TB.  Humans are also dramatically effected by enteric infections, and most of the enteric infections of animals can be immediately transferred to humans and infect humans by the meat and animal products that are contaminated by enteric bacteria from the animals.  If the above history for TB is valid for the continued mis-use of antibiotics for enteric problems of farm animals, it seems reasonable to assume at some point in the future, as many as 70% of human enteric infections will no longer be treatable by antibiotics.

That means thousand to millions of people will die each year from untreatable enteric diseases due to the mis-use of antibiotics that has already occurred, or what will soon occur if we allow the destruction to continue due to some unknown suicidal tendency.

So what are the long term consequences for ignoring the consequences of mis-use of antibiotics for the last 46 years (ie. 1969 Swann Report to today), and plan on continuing this Russian Roulette for another 46 years?

Tragedy of the Commons

I suggest that the mis-use of antibiotics is a sad example of the "Tragedy of the Commons", which is quickly killing the world's "Antibiotic Commons".

To protect the Antibiotic Commons, what is prohibited directly (ie. domestically) must be prohibited from occurring indirectly (ie. in foreign jurisdictions).

We only have one world.  For antibiotics and their mis-use, what is done by one person eventually affects all persons.  No man nor nation is an island unto themselves.  Rules to protect the Antibiotic Commons must be consistent everywhere, or all of us will eventually suffer from the weakest link in the world-wide chain of antibiotic use (or mis-use) that binds us all.

"The last capitalist we hang shall be the one who sold us the rope.”

Karl Marx, German economist & Communist political philosopher (1818 - 1883)  

Is there an equivalent quotation for governments, Big Ag, and Big Pharma and their 46 year co-operation and insistence on the mis-use of antibiotics in agriculture?  

Dr. Elinor Ostrum won the Nobel Prize in Economics for showing that the Commons is not always a tragedy.  Dr. Ostrum had her summer cottage on Manitoulin Island, about 15 km. from my home.  In her research, she gave numerous examples where individuals and communities had developed systems to protect their particular Commons, and enhance it; making their Commons a sustainable resource for hundreds of years.

These positive examples can be used as a catalyst to develop solutions to protect and enhance the Antibiotic Commons.

The Montreal Protocol for reducing ozone depleting substances is generally the best example of co-ordinated international action to protect a Commons; in that case, the Ozone Commons.

I suggest that the Antibiotic Commons is no less important than the Ozone Commons. 

Time To Act

The time for action is now, before it's too late.  We cannot afford to waste another 46 years, distracted by the lobbyists of Big Ag and Big Pharma; two of the biggest and most powerful lobbyist groups in the world.  

Once again, the world has been warned; this time by MCR-1.

When will we listen, learn, and change our behaviours for the better?


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