November 2, 2018

If you don’t use it, you might not lose it!

Since the beginning of time, there has been an microbial tête-à-tête, a battle royale against warring micro-(and not-so-micro) organisms. Only the strong would survive – any phenotype conferring the ability to withstand the harsh realities of competition for scarce resources ensures that this trait will become sustained in the population of organisms bestowed with its presence.

Natural antibiotics are one such compound that, through natural selection, conferred upon its possessors the ability to kill other bacteria who are competing for the same scarce resources. The fungus Penicillium notatum, for instance, produces the substance we’ve all come to know as penicillin – commercially produced, it’s that white gold substance able to kill bacterial disease and pestilence caused by Gram positive and anaerobic bacteria. Through a series of serendipitous events, scientific innovation, regulatory cooperation, and forward-thinking commercialization, the human race was successfully able to discover and mass produce penicillin, thus ushering in the antibiotic era and revolutionizing modern medicine and public health. We had finally won the battle against nature! Case closed. Well, maybe not …

Nature fights back

“The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.” Sir Alexander Fleming, Scottish physician and microbiologist credited with discovering penicillin

Through the same wonderful natural selection process that increased the frequency of antibiotic production in the populations of certain organisms, so too did organisms develop the ability to fight back – to survive in the presence of these potent antimicrobial molecules. Nature being what it is, there is always a tendency to settle into an equilibrium – populations rise and fall as the battle for supremacy rages on … Humans, by harnessing antimicrobials for our own ends, have vastly thrown this delicate balance out of whack, and nature is fighting back with a vengeance in the form of a concomitant and ever-increasing rise in antimicrobial resistance elements.

Common scientific wisdom has led experts to the recommendation to reduce the use of antibiotics. Decreasing use will remove the selective pressures that promote the maintenance of antimicrobial resistance in populations … “if you don’t use it, you lose it”. There is a good deal of research that has noted a reduction in the frequency of antimicrobial resistance in bacterial populations where there has been an effort to reduce the use of antimicrobials. This makes sense, as these resistance elements come at an energetic cost to the microorganism, and when the need for such elements is no longer there (e.g. no more antibiotics!), there is no selective advantage, and these microorganisms will get out-competed by other strains or species that do not need to maintain these energetically costly elements.

Common wisdom might not be 100% wise

New research by Lopatkin et al (2017) illustrates that, even after bacterial populations are no longer exposed to antimicrobials, they STILL can maintain plasmid-mediated resistance within their populations. How in the world can this be?

The researchers looked at plasmid-mediated resistance in E.coli species. Plasmids are genetic elements that are distinct from bacterial chromosomes. They are mobile (can transfer between unrelated bacteria), and can also be passed on to subsequent generations. When they harbor antimicrobial resistance genes, these genes are not only propagated through bacterial generations, they are also spread to unrelated bacteria in close proximity, potentially leading to an exponential increase in prevalence.

For this study researchers removed antibiotic exposure, expecting resistance to be reduced in the subsequent population of E.coli. This did happen; however, the resistance plasmids continued to be maintained within the population, despite being very energetically costly. Through a series of complex experiments, they determined that the transfer of plasmids between unrelated bacteria occurs at sufficiently high of a rate as to ensure their maintenance within the population of E.coli, despite removing the selective pressure of antibiotics.

What does this mean?? This research proves that, despite a reduction in the prevalence of antimicrobial resistance elements within populations when the selective pressure of antimicrobial exposure is removed, that these genes could continue to survive within the population – just waiting to pounce on unsuspecting antibiotics when used again! A wicked problem just may have gotten wickeder.

All is NOT lost… Stewardship, Stewardship, Stewardship!

These results demonstrate that it might not be possible to completely eliminate antimicrobial resistance from populations of bacteria. For one thing, the quoted study was conducted in a lab situation with a single species of bacteria – who knows if this situation holds for the hundreds of billions of other bacterial species in a real-world situation. Also, the story doesn’t change – reducing antimicrobial use DOES reduce the development and dissemination of antimicrobial resistance. All who use antimicrobials need to follow the 5-R approach to antimicrobial stewardship (Page et al., 2014):

Responsibility – accountability of everyone who uses antimicrobials;
Reduction – reducing the quantity of antimicrobials used;
Refinement – the right drug, at the right time, at the right dose, for the right duration;
Replacement – use of other drugs to fight infections;
Review – constant measurement with periodic efforts to critically evaluate and refine the use of antimicrobials.
In addition, the research provides a path forward towards the goal of further reducing antimicrobial resistance. Research efforts should be focused on inhibiting plasmid transfer and promoting plasmid loss.

All is not lost. We can, and must, slow the development and dissemination of antimicrobial resistance.

 

The Farmed Animal Antimicrobial Stewardship Initiative

References

Lopatkin, A. J., Meredith, H. R., Srimani, J. K., Pfeiffer, C., Durrett, R., & You, L. (2017). Persistence and reversal of plasmid-mediated antibiotic resistance. Nature Communications, 1–10.

Page, S., Prescott, J., & Weese, S. (2014). Antimicrobial resistance: The 5Rs approach to antimicrobial stewardship. Veterinary Record, 175(8), 207–208. https://doi.org/10.1136/vr.g5327

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