The Origins and Impact of Antimicrobial Resistance

Microbes

Microbes are very small organisms visible only with the help of a microscope. They include bacteria and related organisms, viruses, and some types of fungi. Microbes inhabit almost all environments including soil and water, and live on the surfaces of larger organisms and within their digestive and respiratory systems. Although small in size, they may be present in great numbers - for example, in the average healthy adult human, there are 10 bacteria for every human celli. Most microbes are not harmful, and in fact many are beneficial to their hosts. Some assist in the digestion and absorption of nutrients, and even those which don't appear to have a specifically beneficial role serve to crowd out harmful species.

Pathogens and Antimicrobial Drugs

A few microbes are pathogens (disease causing) and although animals have an immune system to combat them, it may be outgunned or over-run. In these cases we have come to rely on antimicrobial drugs to help fight them and restore the health of the animal (or person). However, over time, a species or sub-species of microbe can acquire the ability to defend itself against an antibiotic to which it was formerly susceptible. This is called antimicrobial resistance (AMR), illustrated in Figure 1. The occurrence rates of AMR and the speed with which AMR can spread between animals, humans and the environment, locally, nationally and globally have been increasing. This is dramatically decreasing the usefulness of antimicrobial drugs in both veterinary and human medicine.

Two carbapem-resistant Klebsiella pneumoniae bacteria (yellow ) and human white blood cell (green)

Figure 1. Two carbapenem-resistant Klebsiella pneumoniae bacteria (yellow ) and human white blood cell (green)

Credit - National Institute of Allergy and Infectious Diseases [digitally-colourized scanning electron micrograph]

Natural Antimicrobial Resistance

Prominent microbiologist Dr. Tim McAllister (AAFC, Lethbridge) stated that for millions of years before more complex organisms evolved, microbes were at war with each other for resources and living space. As part of an unending arms race, they produced various compounds which were toxic to competitors. The most successful of these antimicrobials killed almost all members of a competitive species. However, in some cases a few fortunate individuals who had an inherent ability (due to random genetic mutations) to resist the toxin would survive. They reproduced and passed on their resistance genes to future generations. This selection process created a resistant population against which that toxin was no longer effective. In essence, the introduction of any antimicrobial compound in a given bacterial population will select for the development of resistance to it.

Resistance to Antimicrobial Drugs

The antimicrobial drugs that we use today (such as penicillin and erythromycin) have their origins in compounds which previously existed in the natural world. The antimicrobial drugs we use in agriculture and human health settings are either purified naturally occurring antimicrobials; synthesized versions of these compounds; or have been constructed with great similarity to natural antimicrobials. This means that even prior to the first use of a "new" antimicrobial drug, it is likely that at least some bacteria somewhere already possess resistance genes, which will be at least partially effective in defending against it. One example of pre-existing resistance comes from bacteria sampled from a cave in New Mexico, which had been isolated from the rest of the world for 4 million yearsiii. Testing found several strains of bacteria with resistance to 14 of the antibiotic drugs currently in use, such as erythromycin, trimethoprim and streptomycin. This remarkable discovery showed conclusively that resistance to many veterinary and medical antibiotics existed in microbial populations long before they were used by humans.

Scientists have developed a library of genetic resistance elements which have been found in various bacteria from different locations. Currently, this database contains 3,111 unique elements, indicating that a large array of resistance genes are scattered across the world in various bacterial species and strains. McAllister notes that the selection for and transfer of pre-existing resistance genes is responsible for almost all of the AMR we are seeing today. He asserts that new spontaneous mutations for resistance are relatively rare events in the natural world, although under laboratory conditions this can be accelerated.

How Does Antibiotic Resistance Spread?

Bacteria are adept at sharing AMR genetic elements. They have several methods of conveying resistance among individuals, even without a direct challenge by an antimicrobial drug. This happens because adjacent individuals actively trade genetic resistance genes as part of normal "social" behaviour. Since different resistance genes may be located close together on the DNA strand, one transfer event may convey resistance to multiple antimicrobial drugs. In addition, this sharing can occur between different species of bacteria.

The spread of resistance genes can occur via microbes living in the soil and water. Resistance elements are passed sequentially through adjacent microbial populations across significant distances, and may appear in distant bacteria which have never been exposed to a particular antibiotic. These pathways can account for the presence of AMR bacteria in cattle on farms with no history of antibiotic use (see Figure 2). In this study, farms with a "natural" production system (no antibiotics used) still had a relatively high prevalence of tetracycline -resistant and MLS1 -resistant bacteria in cattle fecal samples.

AMR Class Abundance in Natural vs. Conventional Operations

Figure 2. AMR Class Abundance in Natural vs. Conventional Operations(1)iv

1MLS = Macrolides, lincosamides, streptogramines

Text Equivalent of Figure 2

Increasing air travel of people around the world has accelerated the transfer of resistance genes among continents. Geographic separation is no longer an effective buffer against resistance occurring in distant places. This is illustrated in Figure 3. The bacteria Klebsiella pneumoniae is a pathogen of humans, causing pneumonia. Carbapenems are antibiotics typically used to treat multidrug- resistant bacteria. The KPC gene, which confers resistance to carbapenems was first found in K. pneumoniae in a hospital in North Carolina in 2000. By 2005 it had spread to three other continents. Figure 3 also shows how another carbapenem resistance gene (NDM) first reported in Sweden was traced back to India, and has spread to North America.

Map of the world showing North America, Africa, parts of Europe and Asia. Red lines show flights from Israel and New Delhi to points around the world.

Figure 3. Global movement of antibiotic resistance genes.

Credit - Nature News

Summary and Implications

Many of the antimicrobial drugs which have been developed are used both in veterinary and human medicine. Resistance genes, which can render specific antibiotics ineffective, occur in bacteria found in livestock, humans and the general environment. These genes can be readily transferred between individual bacteria within a species, as well as across microbial species, leading to the rapid development of bacterial populations that do not respond to drug therapies. This has serious health consequences for both livestock production and people.

Resistance genes can flow through ecosystems, mediated by many bacterial species. This includes bidirectional flow between livestock operations and human communities. They can also be transported across vast distances via modern air travel. The complexities of AMR occurrence, amplification and flow through the environment must be taken into consideration when formulating strategies to combat resistance. The development of AMR cannot be stopped, but it may be delayed as part of a strategy to preserve specific antibiotics for the treatment of serious disease.

Further Reading

References

i American Society for Microbiology. "Humans Have Ten Times More Bacteria Than Human Cells: How Do Microbial Communities Affect Human Health?" ScienceDaily. ScienceDaily, 5 June 2008.

ii McAlister, T. Dec. 2015. Overview of AMU, AMR and Alternative Research and emerging priorities. Beef Value Chain Workshop. Calgary AB.

iii Bhullar, K. et al. (2012) Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS ONE 7(4): e34953. doi:10.1371/journal.pone.0034953

iv McAllister - Morley Laboratory, Lethbridge Research Station, Agriculture and Agri-food Canada.


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