Introduction

On September 1928, Alexander Fleming, Professor of Bacteriology at St. Mary’s Hospital in London was sorting through petridishes of Staphylococcus culture when he noticed that one of the petridishes had a growth of mold. He noticed interestingly that the zone around the mold was clear of bacteria. This indicated that the mold was producing a “mold juice” that was inhibiting bacteria growth. This observation led to the discovery of penicillin and its therapeutic application as an antibiotic. Since then antibiotics have been used in humans and livestock to effectively treat and prevent diseases caused by bacteria, and to promote growth in livestock. However, bacteria have proven to be adaptable, finding ways to develop resistance and necessitating the development of more and more antibiotics. At least 6000 different antibiotics are reported to have been developed; each taking between 5-10 years to come to market, at a cost in the millions of dollars. At the same time, it takes less than a year for a bacterium to develop partial adaptation, and 5 years to acquire full adaptation to a new antibiotic drug (Mikhaleva, 2018). In this article, you will learn why antibiotic resistance is rising, how bacteria acquire antibiotic resistance, and how to reduce antibiotic resistance.

Why the Rise of Antibiotic Resistance

The amazing capacity of bacteria to adapt has resulted in the annual death of 35,000 people of the more than 2.8 million infected each year with antibiotic resistance (AR) bacteria in the US (CDC, 2019). Cully, 2014 reported that in many developed countries, 50-80% of total antibiotics are attributed to livestock. Pets, aquaculture, and crops account for 5%, and humans consume the rest. According to Thomas et al. (2019) on a global scale, 73% of all antibiotics sold are used in animals raised for food. This has led to high antibiotic-resistant rates in livestock, with the highest resistance seen against tetracycline, sulfonamide, and penicillin (Thomas et al, 2019). In 2010 the global use of antibiotics was 63,151 ± 1,560 tons and was predicted to increase by 67% by 2030. A third of this growth is imputed to the scaling up of production in middle-income countries (Van Boeckel, 2015).

How Bacteria Resist Antibiotics

Livestock production, therefore, plays a major role in the emergence and transmission of antibiotic-resistant microorganisms (ARMs). Acquired resistance is caused by multiple mechanisms. For example, the inability of antibiotics to get into target cells, the production of enzymes capable of destroying antibiotics, the excretion of the antibiotics out of the cell via efflux pumps, the modification of intracellular targets, and the creation of alternative metabolic pathways (Mikhaleva, 2018).

As bacteria develop these resistant characteristics, they are able to transfer their new capabilities to other bacteria they interact with through horizontal gene transfer (HGT). This occurs when bacteria pick up free-floating DNA plasmids shed by other bacteria (transformation); when DNA is moved from one bacteria to the next by bacteriophages (transduction); or when DNA is transferred between bacteria through a tube between cells (conjugation) (Gebreyes and Wittum, 2017). Therefore, as long as diverse bacteria populations continue to interact, they will share their genes.

Transfer of Bacteria Resistance Between Reservoirs

The diagram below illustrates the complex cross-interactions of bacteria between major reservoirs. For example, livestock can directly infect humans with ARMs or transfer them via their fecal matter to the soil, irrigation water, and ultimately to the crops we eat.   

10 Ways to Reduce Antibiotic Resistance in Humans

Based on our understanding of how ARMs evolve and spread, we can apply appropriate strategies to control them. These strategies may include:

1. Maintaining the ban on antibiotics in feed
2. Using antibiotics for treating diseases sparingly
3. Reducing the use of antimicrobials in feed. High levels of antimicrobial metals such as copper and zinc used to promote feed efficiency and growth have been found to promote antibiotic resistance (Jacob et al. 2010) 
4.  Following routine vaccination plans
5. Applying good farm management practices such as avoiding overcrowding, isolating sick animals, burying deceased animals, cleaning stables, and drinking trough, and controlling insect pests (Ma et al., 2019)
6. Collecting and treating manure to reduce ARMs
7. Implementing proper disinfection of sewage water to reduce ARMs. Unfortunately, the elimination of ARMs does not necessarily guarantee the removal of all antimicrobial resistant genes (ARGs). ARGs can be transferred to bacteria by transformation and transduction (Dodd, 2012) 
8. Segregation of wildlife from cattle using fencing, or/and the use of livestock protection dogs (LPD) to ward off predatory wild animals such as wolves, coyotes, deer, and wild birds which are frequent carriers of ARMs (Gehring et al., 2010 and Alcalá et al. 2016)
9. Controlling wildlife population through culling or banning people from feeding wild animals (Ma, et al. 2019)
10. Manipulating the gut microbial population of livestock through fecal microbiota transfer. This has worked successfully in human trials where healthy microbiota was transferred to the large intestine to depopulate ARMs (Bilinski et al., 2017)

In the meantime, Scientists will continue to develop new antibiotics to pile on to the thousands already created; just to be eventually outsmarted by this single-cell indomitable enemy. The discovery of a multi-mode-of-action silver-bullet antibiotic is on, but alas, it’s probably a long way off.

References

1. Alcalá, L., Alonso, C., Simón, C., González-Esteban, C., Orós, J., Rezusta, A., Ortega, C., & Torres, C. (2016). Wild Birds, Frequent Carriers of Extended-Spectrum β-Lactamase (ESBL) Producing Escherichia coli of CTX-M and SHV-12 Types. Microbial Ecology, 72(4), 861–869.
2. Bilinski, J., Grzesiowski, P., Sorensen, N., Madry, K., Muszynski, J., Robak, K., Wroblewska, M., Dzieciatkowski, T., Dulny, G., Dwilewicz-Trojaczek, J., Wiktor-Jedrzejczak, W., & Basak, G. W. (2017). Fecal Microbiota Transplantation in Patients With Blood Disorders Inhibits Gut Colonization With Antibiotic-Resistant Bacteria: Results of a Prospective, Single-Center Study. Clinical Infectious Diseases, 65(3), 364–370.
3. CDC. 2019. More people in the United States dying from antibiotic-resistant infections than previously estimated. Available from https://www.cdc.gov/media/releases/2019/p1113-antibiotic-resistant.html. Accessed 05/22/20
4. Cully, M. (2014). Public health: The politics of antibiotics. Nature, 509(7498), S16–S17.
5. Dodd, M. C. (2012). Potential impacts of disinfection processes on elimination and deactivation of antibiotic resistance genes during water and wastewater treatment. Journal of Environmental Monitoring, 14(7), 1754–1771.
6. Gebreyes, W. A., Wittum, T., Habing, G., Alali, W., Usui, M., & Suzuki, S. 2017. Spread of antibiotic resistance in food animal production. In C. E. R. Dodd et al. (Eds.), Foodborne diseases (3rd ed.). Philadelphia, PA: J.B. Lippincott. 
7. Gehring, T. M., VerCauteren, K. C., Provost, M. L., & Cellar, A. C. (2010). Utility of livestock-protection dogs for deterring wildlife from cattle farms. Wildlife Research, 37(8), 715–721.
8. Jacob, M. E., Fox, J. T., Nagaraja, T. G., Drouillard, J. S., Amachawadi, R. G., & Narayanan, S. K. (2010.). Effects of Feeding Elevated Concentrations of Copper and Zinc on the Antimicrobial Susceptibilities of Fecal Bacteria in Feedlot Cattle. Foodborne Pathogens and Disease, 7(6), 643–648.
9. Ma, Z., Lee, S., & Jeong, K. C. (2019). Mitigating Antibiotic Resistance at the Livestock-Environment Interface: A Review. Journal of Microbiology and Biotechnology, 29(11), 1683–1692.
10. Mikhaleva, T. V., Zakharova, O. I., & Ilyasov, P. V. (2019). Antibiotic Resistance: Modern Approaches and Ways to Overcome It (Review). Applied Biochemistry & Microbiology, 55(2), 99–106.
11. Van Boeckel Thomas P., Brower Charles, Gilbert Marius, Grenfell Bryan T., Levin Simon A., Robinson Timothy P., Teillant Aude, & Laxminarayan Ramanan. (2015). Global trends in antimicrobial use in food animals. Proceedings of the National Academy of Sciences of the United States of America, 112(18), 5649.
12. Van Boeckel, T. P., Pires, J., Silvester, R., Zhao, C., Song, J., Criscuolo, N. G., Gilbert, M., Bonhoeffer, S., & Laxminarayan, R. (2019). Global trends in antimicrobial resistance in animals in low- and middle-income countries. Science, 365(6459), 1266 

Courtney Simons

Administrator

Dr. Simons is a food science educator. He earned his bachelor’s degree in food science, and Ph.D. in cereal science at North Dakota State University.