Of Pigs, Bugs, Drugs and Genomics: The Smoking Gun for Antibiotics on the Farm

This is a story that begins generations ago. Shortly after World War II, the makers of antibiotics realized that supplementing animal feed with antibiotic containing byproducts increased agricultural productivity.  Antibiotics were the miracle drugs of WW II, and at the time this seemed like yet another benefit.  However, by the 1970s, the emergence of resistant bacteria was becoming an increasing problem in medicine.  In seminal work, Levy showed that the introduction of antibiotic supplemented feed on a poultry farm led rapidly to changes in the gut bacteria of both the chickens and the workers on the farm, and to the emergence of bacterial strains resistant to the antibiotic in the feed.  Their article concludes:

“The present findings clearly demonstrate, however, that antibiotic-supplemented feed is a factor contributing to the selection of human resistant strains of bacteria. These data speak strongly against the unqualified and unlimited use of drug feeds in animal husbandry and speak for re-evaluation of this form of widespread treatment of animals.”

And that is how things sat for more than 40 years.  The agricultural industry argued that antibiotics were important in raising productivity, the drug companies sold literally tons of antibiotics in the agricultural market, shortly after each new generation of antibiotic was introduced in human medicine, they were distributed to the agricultural market, and shortly after that resistant strains emerged requiring the development of ever more potent (and expensive) new antibiotics.

If you think about it, feed supplements create nearly an ideal environment for the emergence of bacterial resistance.  The drugs are given at subtherapeutic doses to large populations of bacteria.  A few partially resistant variants gain selective advantage in this context, and as they proliferate and evolve greater resistance, they achieve even greater selective advantage until eventually they dominate the bacterial flora of the animals on the farm.

Unfortunately, farms are not research laboratories.  Workers are constantly and intimately exposed to waste products and aerosols as they care for animals, clean stalls and dispose of waste.  Thus it is not surprising that resistant strains could be passed from farm animals to human workers.  What is less obvious is that the farm animals might pick up bacteria from their human handlers.

Move the clock forward to 2012 and the era of modern genomics and inexpensive genome sequence analysis.  A multinational team showed that multiply resistant Staphylococcus aureus (MRSA; an important medical pathogen and public health threat) moved from humans to pigs, acquired additional antibiotic resistance, and moved back to humans.  They did this by sequencing the complete genomes of 88 bacterial isolates from multiple sources, a task that would have been unthinkable only a few years ago.  By sequencing the complete genomes, they were able to detect the minute genetic variations that all organisms acquire randomly from generation to generation (single nucleotide polymorphisms or SNPs).  By comparing the patterns of SNPs, they could determine which isolates were derived from which parental populations thus tracing the history of MRSA infection in pigs and its reintroduction in an even more resistant form back to humans.  This is the smoking gun that closes the loop and shows that not only does antibiotic use on the farm lead to resistant strains, but that it can directly lead to increased resistance in important human pathogens.

Finally, after 45 years, the FDA has issued rules beginning to govern antibiotic use on the farm.  Of course, MRSA did not exist back in 1974 when Levy et al. published their paper, and we now spend scarce resources tracking MRSA in the hospital and community.  And we are losing patients to untreatable infections.

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