Antibiotics & Agriculture Part 4: The Transfer of Antibiotic Resistance

The patient was in dire condition. A forty year old woman from Michigan, she had suffered badly from diabetes, kidney failure and a number of complications related to those diseases. Two years after she had started dialysis, disaster struck. She developed painful foot ulcers, and an infection in her leg that was so severe that the whole leg had to be amputated. What was worse was that immediately after the operation, her amputation wound became infected, with Staphylococcus aureus. In her only stroke of luck that day, the Staphylococcus aureus was susceptible to antibiotics. But the next year, the foot ulcers were back, and she required even more amputations, as well as treatments to prevent the bacterial infections causing these ulcers from becoming fatal.
The catheter that linked her blood to the hospital's dialysis machine, the replacement for her riven kidneys, provided Methicillin-Resistant Staphylococcus aureus with easy entry into her blood. There was only one antibiotic that could stop this MRSA infection. Vancomycin was given to the patient while the physicians removed the infected catheter. In its place, the physicians used a number of temporary catheters, to ensure that the patient could still use the dialysis machine.
But a number of these catheters also became infected. When the physicians examined these catheters, they realised that against all odds, things had taken a turn for the worse. They discovered that the Staphylococcus aureus on this catheter had been joined by Vancomycin resistant Enterococci. Now the Staphylococcus aureus were resistant to Vancomycin too.  They searched all of the possible options that could have lead to this situation, and it was the DNA evidence that revealed what had happened. The Vancomycin resistant Enterococci, commonly found in the community but rarely infectious, had given its resistance genes to MRSA.

This was the first of a series of outbreaks of VRSA that occurred in Michigan, and all of them had a similar theme. A person with an MRSA infection would spontaneously develop full blown resistance to vancomycin out of nowhere. The only commonality in all of these cases was the presence of vancomycin resistant Enterococci both before and during these cases. So how did vancomycin resistant Enterococci pass along their resistance to MRSA ?
The answer lies with DNA molecules known as plasmids.

 These are rings of DNA which can carry genes between different bacteria. The exchange of plasmids between bacteria is a key driver of bacterial evolution, as it allows species to share genes between eachother. They enable bacteria to acquire new traits from other bacteria in the vicinity, which can allow them to adapt to their environment in new ways. In this case, the vancomycin resistance "trait" was carried on a plasmid in Enterococci, and this plasmid could be very easily transferred to Staphylococcus aureus.  The high abundance of Enterococci with vancomycin resistance increased the probability of this occurring.

This constant transfer of plasmids between bacteria plays a key role in their evolution. It allows a bacterium entering a new environment to steal some useful genes from the bacteria that are already there, helping it adapt to that niche. This is what happened in the cases discussed above, and is one of the more insidious methods through which antibiotic resistance can spread.
As we've seen in the previous posts, the unregulated use (and in some cases regulated use) of antibiotics in agriculture leads to the evolution of new resistant strains of bacteria. These strains can exchange this resistance using plasmids. The transfer of these plasmids to human pathogens is a major threat to human health.

Making things worse is that some plasmids can carry multiple resistance genes, rendering a variety of different antibiotics useless. The problem with using antibiotics in agriculture comes primarily from increasing the net amount of these non-pathogenic bacteria with resistance genes.

In the above case study, we have seen that Enterococci can exchange its resistance with Staphylococcus aureus. But we only know about Enterococci because on rare occasions, they can cause disease in humans. We don;t keep a track of all of the bacteria that don't cause disease. These are the bacteria that live in our bodies, that help us digest food and maintain an immune system. we are constantly exchanging these bacteria with our environmental surroundings.
 They live under the radar, and nobody notices when they develop antibiotic resistance. Since they never cause disease in humans, we never need to prescribe antibiotics against them. The only time they would encounter sustained levels of antibiotics is on a farm, where they are constantly infused into the feeds of their animal hosts. Here they can evolve new resistances, and when they get transferred to humans, can exchange their antibiotic resistances with the bacteria they find in their new niche.
It is difficult for us to tell what kind of resistances an invading pathogen could potentially pick up from these bacteria.
To use an analogy, these silent bacteria may act as weapons merchants, hoarding resistances until the can share them with one of our potential enemies.
One way for researchers to investigate this is to simply take a snapshot of bacteria within an area, and just test for the resistance genes. Instead of looking for the weapons merchants, they are focussing on checking for the weapons.
 With this technique, the scientists directly checked for the presence of resistance genes in an environment. This is known as the “resistome”.
Recently a group of researchers took it upon themselves to catalogue the “resistome” of three different countries.  They compared the types of resistances they found in different countries to the way antibiotics were used in each of them.
The types of antibiotics that bacteria were resistant to were slightly different in each of the three countries they investigated (USA, Spain and Denmark). The antibiotics to which bacteria were most commonly resistant were the ones that were approved for use in animals. Antibiotic resistances were lowest in the places that had the ban in place for the longest time.
This all indicates that the agricultural use of antibiotics has contributed to the creation of a number of antibiotic resistant bacteria, but increased the number of resistance genes in our environment available for other pathogens to become resistant.
The mountain of evidence is indisputable. There is no doubt that new strains of antibiotic resistant bacteria owe their genesis to the reckless use of the drugs on farms. But is it fair for farms to take on the full brunt of the blame for the fall of antibiotics ? Would we not have antibiotic resistant bacteria in our hospitals even if the farms had banned them ?
I'll be dealing with this question in the conclusion of this series next time.

To be continued.....

References

Chang S., Sievert D.M., Hageman J.C., Boulton M.L., Tenover F.C., Downes F.P., Shah S., Rudrik J.T., Pupp G.R. & Brown W.J. & Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene., The New England journal of medicine, PMID: 12672861

Zhu W., Murray P.R., Huskins W.C., Jernigan J.A., McDonald L.C., Clark N.C., Anderson K.F., McDougal L.K., Hageman J.C. & Olsen-Rasmussen M. & (2010). Dissemination of an Enterococcus Inc18-Like vanA Plasmid Associated with Vancomycin-Resistant Staphylococcus aureus, Antimicrobial Agents and Chemotherapy, 54 (10) 4314-4320. DOI: 10.1128/AAC.00185-10

Forslund K., Sunagawa S., Kultima J.R., Mende D., Arumugam M., Typas A. & Bork P. (2013). Country-specific antibiotic use practices impact the human gut resistome., Genome research, PMID: 23568836