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September 28, 2016

How the link between human diseases and livestock AGPs was established

By ERIC J. BROOKS

An eFeedLink Hot Topic
 
  • Both the benefits of AGPs and problems with bacterial resistance where discovered almost as soon as antibiotics were introduced 
  • The link between antibiotic resistance and AGPs was made in the 1970s but their role in human disease was not proven at the time 
  • From the mid-1990s to late 2000s, the rapid spread of MRSA infections and their infection of famous professional athletes stimulated new research into possible links with livestock AGP use 
  • The past five years has seen a rising number of scientific studies form increasingly stronger associations between human illness and the use of AGPs
The ability of antibiotic growth promoters (AGPs) to boost livestock growth was discovered by accident in 1948 at Lederle Laboratories (which is now part of the Wyeth Pharmaceutical Group). At the company's R&D division, senior Lederle animal nutritionist Robert Stokstad and biochemist Thomas Jukes, a biochemist, were using vitamin B12 to try and accelerate broiler growth in a manner that would boost feed conversion ratios (FCRs).
 

Because synthetically produced B12 was expensive, these researchers opted to inject poultry with the cellular remains of Streptomyces aureofaciens bacteria, which are naturally rich in this vitamin –but which by coincidence also had naturally high levels of tetracycline.
 
Soon, Stokstad and Jukes began to suspect that tetracycline was more critical to broiler growth than the B12 itself. In a follow up experiment, broilers given B12 from bacterial remains (which contained tetracycline) grew 24% more than those given the same B12 dosage extracted from liver (which did not contain tetracycline).
 

The biochemical process by which this occurred would not be understood for years. Even so, researchers soon discovered that at low dosages, an entire array of different antibiotics had a similar growth boosting effect on various livestock species. Best of all, when antibiotics were administered in AGP doses, profoundly improved FCRs coincided with an ability to boost stocking densities to levels previously not possible.
 
These discoveries had an immediate, highly profitable impact on livestock returns. With the starting of modern aquaculture, similar productivity boosting effects were observed in almost all cultivated seafood species. This jump-started a sixty-year era of routinely administering antibiotics at low, AGP level doses to farmed livestock and cultivated seafood species.
 
Thus, by the late 1960s, over 80% of the antibiotics sold worldwide were administered to animals instead of people. What matters is not just that bacteria had four times as many opportunities to develop antibiotic resistance in animals than in human but how conducive animal environments were to the accelerated development of resistance.
 
Sir Alexander Fleming, who discovered the first antibiotic, predicted from as far back as the early 1940s that uncontrolled use of antibiotics would lead to the evolution of resistant bacteria. –What Fleming could not predict however was that the reservoir of antibiotic-resistant bacteria would develop not in hospitals but at farms -or that making a definitive link between agribusiness and bacterial resistance would take decades.
 
In hindsight, antibiotics ability to transcend housing density limits and make unsanitary conditions into cost savings further accelerated their already speeded-up evolution of resistance. Livestock greatly outnumbered human patients and were raised in far less hygienic, bacteria-rich environments. Whereas humans usually took antibiotics for a limited period of time, integrated farms featured constant, decades-long interaction between antibiotics and heavy bacterial populations.  
 
Animal intestines, manure and slaughtered remains hosted massive reservoirs of both different antibiotic types and different pathogenic species at the same time. Within decades, it was discovered that bacteria are capable of sharing and transmitting antibiotic resistant DNA to their fellow bacteria and even across different species. This made researchers speculate that integrator housings acted as giant 'reactors' which were greatly accelerating the evolution of bacterial resistance faster to antibiotics faster than we could develop them.
 
Indeed, no sooner were antibiotics used in livestock that significant resistance in penicillin was observed by the mid-1950s, especially in Staphylococcus aureus. At this time however, livestock AGPs were not implicated. Even so, to try and preserve its medicinal value, penicillin was restricted to prescription use. Out of concern for growing resistance to penicillin, in 1960, methicillin, a narrow-spectrum β-lactam antibiotic was developed to ensure that serious human infections could still be treated.
 
For the first two decades, although bacterial resistance to antibiotics was observed in human infections, no researchers linked it to livestock farming until 1976. That year, Stuart Levy, a Tufts University physician and researcher named Stuart Levy published a study implicating AGPs. At a farm in Massachusetts, Levy fed chickens tetracycline and within a week, tetracycline-resistant bacteria began to populate poultry gut flora and were detected in their feces. His study was the first major, well publicized research to warn that using AGPs could lead to human infections resistant to antibiotics.
 
While Levy demonstrated the ability of AGPs to induce antibiotic resistance, he did not establish a causative link between them and antibiotic resistant infections humans. Despite the implications of his study, rampant use of antibiotics like vancomycin (which was developed a "last resort" against microbial resistance) as AGPs throughout the 1980's led the development of increasingly resistant strains. Resistance to multiple antibiotic classes was detected in many livestock pathogen populations including Staphylococcus, E. Coli and salmonella.
 
Follow up studies established that bacterial resistance to antibiotics was rising. By the 1980s, scientists were running out of new antibiotic types and classes that could be invented, causing great concern. However, with no proof that this resistance arose from livestock, AGP use continued to expand.
 
In developing countries with nascent, fast growing agribusiness sectors like China and Vietnam, AGPs and therapeutic livestock antibiotics were used far more liberally and with fewer restrictions than in the west. Even new antibiotics like vancomycin (which was developed in response to resistance in older antibiotics) were readily used as AGPs.
 
While no proof existed of a link to livestock AGPs at the time, the early 1990s saw new, highly virulent strains of methicillin resistant staphylococcus bacteria (MRSA) evolved. Within 20 years, it was responsible for half the 23,000 US deaths from antibiotic resistant infections and an even greater number of limb amputations.
 
What was fascinating but frightening about MRSA is that while methicillin had never been used in livestock farms, the DNA plasmids which conferred resistance to chemically related β-lactam AGPs such as penicillin and ampicillin also made ST398 bacterium resistant to methicillin. Apparently, even if a particular antibiotic is not administered to livestock, bacteria can in some cases become resistant to it if an AGP belonging to the same antibiotic class is used.
 
Unlike the past, these MRSA infections even infected healthy people with no pre-existing medical condition or weakened immunity. As the disease spread, victims ranged from hospital patients to American high school athletes and a senior Canadian politician, who was forced to undergo a leg amputation. What drew media attention was how, after the mid-2000s, MRSA spread into professional sports clubs, maimed well known professional athletes and forced a redesign of US sports locker room facilities.
 
From 2005 through 2016 dozens of professional American baseball, basketball and football players including Alex Rios, Kyle Farnsworth, Paul Pierce, Lawrence Tynes and Daniel Fell have –for the first time in the history of their sports– come down with MRSA. The latter two lost significant parts of their foot tissue, nearly required amputation and will never play again.
 
Practices such as shared locker room stools, which had been safely taken for granted for over a century, had to be abolished. The disease's attacking of millionaire sports athletes caught attention of researchers –and stimulated research into the possibility that the new, deadly, MRSA strains evolved on livestock farms using AGPs.
 
The past decade's new wave of research, particularly into MRSA, has changed how we look at AGPs. First, genetics technology was to trace human MRSA cases back to genetically identical bacteria at hog farms. A link between farm worker MRSA infections and AGP use at hog farms was soon also found. Later, bacteria from human MRSA cases and staphylococcus bacteria found in cattle farms and poultry farms were also found to share the same genes to antibiotic resistance –but this in itself did not prove that resistance from AGP use had 'jumped' from livestock farms into the common human population.
 
Proof soon came of how easily antibiotic resistant farm bacteria could spread into a surrounding community: In a 2004 USDA-funded study, Philip N. Smith a researcher at Texas Tech University discovered that, "Tetracycline resistance [in bacteria] was 400,000% more prevalent downwind [from a cattle feedlot] than upwind. At some downwind locations, the tetracycline resistance was in 100% of the [bacteria] samples."
 
More recently, according to an article published in the 26 September 2016 online edition of World Poultry ("Contaminated poultry spread superbug to humans"), a study by Robert Skov at Denmark's Statens Serum Institut and Lance Price, PhD at George Washington University's Milken Institute School of Public Health (Milken Institute SPH) provides strong evidence that people with no exposure to livestock are becoming colonized and infected MRSA that was acquired by eating or handling contaminated poultry meat.
 
--Interestingly, Denmark where both the study and outbreaks took place, banned AGPs over ten years ago. The ten MRSA victims in the study lived in large Danish cities and their bacteria was genetically identical, implying a common origin. Genetic analysis of their MRSA bacteria showed it to be a strain not found in Danish livestock, which are raised without AGPs but found in neighboring European countries from which the chicken meat eaten by victims was imported from. The study concluded that this was "compelling evidence that everyday consumers are also potentially at risk."
 
It findings are re-enforced by studies by the University of Iowa's Tara Smith. In research conducted by Smith over the last five years, she repeatedly detected significant MRSA bacteria levels not only in supermarket meat portions but in some cases, even on grocery cart handles. Her studies frequently also detected the simultaneous presence of salmonella strains resistant to tetracycline –again, genetically traceable back to livestock farms.

Smith's research dovetails with a recent study undertaken by Dr. Mark Holmes of Cambridge University's Department of Veterinary Medicine ("MRSA contamination found in supermarket sausages and minced pork in UK", Science Daily 18 June 2015), which found MRSA bacteria in the fresh ground pork and sausages sold at British supermarkets.

Holmes noted that, "This is the first time MRSA has been detected in retail meat products in the UK." He concluded that, "resistance to antibiotics is a problem that goes far beyond humans", the study implies that, "MRSA is established in our pig farms and provides a possible route of transmission from livestock, through those in direct contact with pigs, into the wider population."

Similar links between supermarket meat and antibiotic resistant infections were also found by America's Centre for Disease Control (CDC). The CDC investigated a 2013-14 US salmonella outbreak that was traced back to supermarket chicken meat. Resistant to several antibiotics including tetracycline and penicillin, the outbreak sickened 647 people in 27 states. CDC researchers traced it back to AGP-raised chicken grown at California-based Foster Farms which the USDA had cited for unsanitary meat processing conditions a whopping 480 times over two years.

Similarly, in late 2015, Britain's Lancet published a study on antibiotic resistant E. Coli hospital infection outbreaks that were traced back to AGP use on Chinese livestock farms ("Emergence of plasmid resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study", 18 November 2015). Colistin-resistant E. Coli bacteria was found in 15% of 523 raw pork samples and 21% of 880 hogs tested across five Chinese provinces.

If some of this article's readers are hostile to the idea that a link between AGP use and serious human diseases has been established, this is understandable: Even less than ten years ago, definitive causal links between urban outbreaks of diseases like MRSA or tetracycline-resistant salmonella were implied but not definitive.

This is now changing: The studies cited above are just a small portion of a growing mountain of evidence linking AGPs use to serious, antibiotic resistant disease outbreaks in urban, non-farm environments. Many more studies like the ones mentioned above are being undertaken at this time, and the results are increasingly predictable. The United Nations recently held a crisis conference on growing antibiotic resistance, declaring it one of the most serious health problems or our time. Amid growing causal linkages between AGPs and human disease, the livestock sector's traditional hostility to restrictions on antibiotic use cannot be tolerated.
 


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