1 – Introduction
1.1 – Section one: An outline of the Problem of Antimicrobial Resistance
1.2 – Section two: Solutions to the Problem of Antimicrobial Resistance
Section 2 – An outline of the Problem of Antimicrobial Resistance
2.1 – Mechanism
a. Relevant layout of the bacteria capable of causing anti-microbial resistance
b. Mutation of the cell
c. Biochemical/Efflux Pumps
2.2 – The Cause
a. The agricultural industry
b. Medical malpractice
c. Failure to regulate
2.3 – The Impact
Section 3 – An outline of the Solutions to Antimicrobial Resistance
3.1 – In Vitro Meat
3.2 – Government spending on research
3.3 – Government legislation and regulation
Section 4 – Conclusion
4.1 – The Impact
4.2 – The Cure
1 – Introduction
This project seeks to outline the problem of antimicrobial resistance. The first section of this document will include a discussion into the mechanics behind the development of resistance in bacteria, the operations within society which are leading to a rise in antimicrobial resistance and the impacts that near-total immunity to antibiotics in bacteria would have on everyday life and society as a whole. The second section of this document will explain the particular routes and avenues in which society can help solve the rising immunity to antibiotics that exists within certain strains of bacteria. This includes an assessment of new potential medical and agricultural practices, as well as government intervention in the marketplace and in the realms of scientific research. Antimicrobial resistance will herein be referred to interchangeably as antibiotic resistance in bacteria, AMR, or antimicrobial resistance. These terms for the purpose of this document will remain interchangeable, although there are nuances between the definitions on a scientific basis. Antimicrobial resistance (AMR) is defined as “when microorganisms such as bacteria, viruses, fungi and parasites change in ways that render the medications used to cure the infections they cause ineffective.” (World Health Organisation 2017), as opposed to antibiotic resistance in bacteria which specifies which strain of microorganism is being affected by the problem of antibiotic resistance.
1.1 – Section one: An outline of the Problem of Antimicrobial Resistance
As stated above, the first section of this document will outline the mechanics of Antimicrobial resistance, this includes the different biological weapons in evolution’s arsenal. The first area which will be discussed is when there are mutations in the outer membrane of gram-negative bacteria which lead to an inability for antibiotics to enter the cell. Secondly, this document will explain how the development of biochemical pumps in bacteria can expel antibiotics, thus defending them against the antibiotics. Furthermore, the first section will also look into the mutation of active sites within bacteria and the addition of enzymes within the line of attack for antibiotics which hamper their effectiveness and lead to antimicrobial resistance.
After the mechanics of antimicrobial resistance have been explained, this document will seek to lay out that which we humans do that leads to antimicrobial resistance, including medical malpractices, farming faux-pas and the frivolous misuse and overuse of antibiotics in unregulated economies and developing nations. Leading on from this, the impacts to wider society, such as the inability to treat diseases which otherwise would we easily treatable, general medical practices such as blood transfusions and organ transplants which would no longer be viable, and the effect it would have on travel and other such wider problems.
1.2 – Section two: Solutions to the Problem of Antimicrobial Resistance
The second section will hopefully be less doom and gloom. Explaining the methods which society could undertake to lessen the effect or reverse the problems of antimicrobial resistance. Section 2, subsection 1 will look into the solutions within the medical sphere, such as more in-depth
Section 2 – An outline of the problems of antimicrobial resistance
Antimicrobial Resistance will be one of the defining issues of the next century. Since their discovery and use, antimicrobial resistance has been found against every strain of antibiotics we have in our arsenal (Centers for Disease Control and Prevention, 2013). Over the last 20 years, different medical professionals and scientists have theorised the coming of the end of antibiotics in society, with “tuberculosis, typhoid fever, meningitis, pneumonia, and septicaemias” emerging as imminent global threats (Quintessence Int. 1998). The development of antibiotics has been on a general downwards trend since their introduction to medical use in the 1940s, with peak antibiotic development occurring around the late 1950s to the early 1960s. (See fig 1.1) Frivolous use and lack of in-depth scientific knowledge regarding antibiotics has likely seen most of the drug’s potential squandered.
Timing of Market Introduction and Emergence of Resistance for Selected Drugs. [fig 1.1] (Alliance for the Prudent Use of Antibiotics, n.d.)
As we entered the 21st century, the level of usable antibiotics has sharply declined. For example, the levels of usable antibiotics for the disease Gonorrhoea (Neisseria gonorrhoeae) currently sits at just one. During the late 1990s and early 2000s, “fluoroquinolone resistance in N. gonorrhoeae emerged in the United States”, by 2007, resistance to fluoroquinalone was so widespread that medical professionals stated that the antibiotic was no longer relevant in the treatment of Gonorrhoea. This left a strain of antibiotics called cephalosporins as the last remaining effective strain of antibiotics in the fights against Gonorrhoea. (Mortality and Morbidity Weekly Report 2007, 2012). Within the cephalosporins antimicrobial class there were two strains effective against N. gonorrhoeae, cefixime and ceftriaxone. Fig 1.2 shows the minimum inhibitory concentrations for both these antibiotics, indicating an elevation in the necessary level of said antibiotics in treating Gonorrhoea infections. This elevation had suggested a waning in the effectiveness of the antibiotics against the strain, and come late 2012 the cefixime strain of antibiotics was entirely ineffective.
This extreme adaptation to antibiotics has not solely occurred in Gonorrhoea however, it is something that has affected a certain type of bacteria almost universally. Due to this, as a society, we may run out of useable antibiotics within the next few decades, and the problems that will bring to society will be immense.
Percentage of Gonorrhoea isolates with elevated cefixime MICs and ceftriaxone MICs
[Fig 1.2] (Centers for Disease Control and Prevention, 2012) MICs = minimum inhibitory concentrations
diagnoses of diseases to determine which form of antibiotic is suitable for treating the symptoms, and also a condemnation of the current malpractices of Doctors prescribing general antibiotics for viral infections, of which these have no healing effects. Subsection 2 will look into the agricultural industry, highlighting how better farming practices would lessen the impact of anti-microbial resistance, and how the current development of In Vitro meat could remove the necessity of using antibiotics within the industry altogether. Finally, within this section, I will sum up the overall government regulations and potential schemes the government has and should put in place to combat the issue of antimicrobial resistance in bacteria.
- Relevant layout of the bacteria capable of causing anti-microbial resistance
[Figure 1.3] (Diagram showing the differing nature between gram positive and gram negative bacteria, 2013)Most antibiotics currently work by attacking the functions of the inner cells, inevitably to do so, they must be able to access the cells themselves. There are two major forms of bacteria, known as gram-positive, and gram negative. [See fig 1.3]
Gram-positive bacteria contain a peptidoglycan cell wall, which acts as a primary defence, past this there is a plasma membrane. This cell wall houses little defence against antibiotics, and because of this, the mechanism for antimicrobial resistance is rarely to do with the outer membrane. However with gram-negative bacteria, in addition to the peptidoglycan cell wall and the plasma membrane, there is also an outer membrane and the periplasm.
Diagram showing the differing nature between gram positive and gram negative bacteria.
- Mutation of the cell
The outer membrane creates a barrier to antibiotics. There are two routes in which an antibiotic can permeate the cell wall. There is a pathway for hydrophobic antibiotics which negates the necessity for diffusion, and general diffusion pores that cross a cellular membrane for hydrophilic antibiotics (Delcour, 2008). Once within the outer membrane, bacteria commonly work by preventing the bacteria from building such a cell wall, this occurs when the antibiotic prevents the molecules which form the cell wall from binding together. An example of an antibiotic which utilises this technique is Beta-Lactam group.
Alternately, the macrolide group of antibiotics work by attacking the ribosomes in the cells of bacteria. Ribosomes function by constructing the proteins, and proteins are what help keep the bacteria cell alive, therefore by attacking the ribosome, the antibiotic will cause the bacteria cell to die (Learn.genetics.utah.edu, n.d.). Random mutations within bacteria can cause a modification in the structure of areas such as the ribosomes and the cell walls. With the macrolide strain of antibiotics, resistances comes either through methylation or mutation of the ribosome which prevents the macrolide from binding to it (Leclercq, 2002).
- Biochemical/Efflux Pumps
Following on from methylation or mutation of the individual parts of the cells, another way in which bacteria gain a resistance is through a process called efflux. Efflux is the mechanism responsible for moving compounds, like antibiotics, out of the cell. (Sun, Deng and Yan, 2014) Efflux pumps are located in the cytoplasmic membrane of the cell and are considered to be active transport pumps. Active transport pumps require energy to function, rather than working by functions such as osmosis, of which would constitute passive transport. Although not necessarily purposeful, cells with efflux pumps also work at expelling antibiotics, and the problem with antibiotics arise due to the fact that the bacteria with efflux pumps are far more likely to survive than those which do not. These bacteria then multiply through the process of binary fission which is a form of asexual reproduction, due to this, other than random minor mutations, the offsprings are genetically identical to the parent cell. Additionally, whilst some efflux pumps are antibiotic specific, many actually operate on multiple drugs.
The final mechanism of antimicrobial resistance this project will cover is enzymatic modification. (Chow, J.W., Mobashery, S., Toth, M., Vakulenko, S.B., 2009) Enzymatic modification is when bacteria produce enzymes which are capable of modifying the respective antibiotic prior to it reaching its target. (De Pascale, G., Wright, G.D., 2010). This, in essence, means that they cannot perform their roles and are thus ineffective. Enzymes that perform such functions commonly exist within the periplasm (see fig 1.3), and as antimicrobial agents via general diffusion make their way across the enzyme and protein-rich body they are modified irreparably. Beta-lactamases elaborated by both gram-negative and gram-positive bacteria hydrolyse what is known as the amide bond of the beta-lactic nucleus destroying the antimicrobial abilities of the beta-lactic agent. (Trevor, Katzung and Kruidering-Hall, 2012)
- The intensive farming industry is one of the largest causes of antimicrobial resistance that we’ve identified. (VMD, 2009) In essence, antibiotics are being used within intensive battery farming to ensure that animals are able to survive in squalid conditions, this is used to reduce the price of meat, and to also increase the amount produced. The average annual per capita cost to consumers in the US were there to be a ban on antibiotic drug use would be $4.84 to $9.72, assuming a U.S. population of 260 million, the total cost to consumers would amount to about $1.2 billion to $2.5 billion per year (National Academies Press (US); 1999). Adjusting for inflation, this sum in 2017 would be up to $3.7 billion.
According to a report produced by an independent body chaired by the British economist Jim O’Neill, farming within the US uses up to 70% of antibiotics which are critical to medical use in human beings (O’Neill, 2015). These antibiotics are used in healthy animals to both speed up growth, and as a preventative measure to stop disease spreading due to the unhealthy conditions the animals are kept in, as a result, the levels of antimicrobial resistance is becoming ever more prevalent – especially within countries that have massively developed economically over the past 20 or so years (Tilman et al., 2002). Due to a lack of regulation, antibiotics which are kept as a last resort to save the lives of human in case of widespread antimicrobial resistance are being used within the farming industry, because of this, bacteria is ever more likely to adapt to become resistant (Hancock, 2017). A recent study from China (STAT, 2017) has shown that some strains of Escherichia coli have developed resistance to colistin, a form of polymyxin antibiotic. This antibiotic is a last resort antibiotic, one of the last effective forms in our antibiotics armoury.
The waste runoff from intensive farming is another major concern when antibiotics are used in farming, there is very little that can be done to prevent these antibiotics escaping into the environment (Karthikeyan and Meyer, 2017). Studies of sludge at wastewater facilities have shown a growing level of resistance across the spectrum. In environments which contain a wide variety of antibiotics, antimicrobial resistance can occur at a far more rapid pace, leading to general concerns of widespread antimicrobial resistance in sewers and streams. These circumstances are the greatest cause of antimicrobial resistance and need to change if we are to tackle the issue. (Compassion in World Farming, 2017).
- Medical Malpractice is another major cause of antimicrobial resistance. Increasingly, antimicrobial resistance is being linked with the volume of antibiotic medication prescribed, as well as general laziness when it comes to taking antibiotics (for example, missing out on a dosage, or finishing the course of antibiotics before it has run its course). (Pechère, 2001). Additionally, the prescription of incorrect of ineffective antibiotics has been attributed with the increasing prevalence of antibiotic resistance. (Arnold and Straus, 2005). Another instance of increasing levels of malpractice among the medical community is in the prescribing of antibiotics when entirely irrelevant. The common cold, for instance, is a viral infection, and antibiotics are entirely ineffective at combating viruses, the prescription of antibiotics to combat a viral infection will have absolutely zero effect on the disease itself, and will only lead to the ever increasing rate of anti-microbial resistance being hastened. Doctors know that in most cases that the common cold is a virus, however, patients feel like they haven’t been treated well if they attend a doctors clinic and receive no medication, so in instances where approval ratings need to be reached, or the doctors want their patients to feel like something has been prescribed to help fix the illness, doctors will prescribe entirely useless medication. According to a study by the Centers for Disease Control (Cdc.gov, 2017) up to half of the antibiotics used in humans are unnecessary and inappropriate.
- Another sociological cause of antimicrobial resistance is a lack of global government regulation. With underdeveloped and individualistic economies allowing the sale of last resort antibiotics without any real recourse or regulation. Many of these antibiotics are strictly regulated in developed countries due to their critical importance and ability to prevent deaths in the extreme cases. In addition to this, the manufacture of antibiotics itself is unregulated, and in China and India, the effect of this is severe. (The Guardian, 2017). The release of wastewater containing particles of antibiotics and general medical contaminants is vastly increasing the rates of antibiotic resistance and is causing the spread of antibiotic ingredients which cause bacteria to develop immunity to antibiotics, creating superbugs. A study of this wastewater found that not only were antibiotic resistant bacteria escaping the filtration system meant to prevent them escaping into the environment. “For every bacterium that entered one waste treatment plant, four or five antibiotic-resistant bacteria were released into the water system, tainting water, livestock and communities”. Recently, 13 pharmaceutical companies signed a declaration aiming for collective action on antimicrobial resistance. This committed them to a review of their manufacturing processes, with the aim of preventing contamination of the wider environment.
2.3 – The Impact
Without effective antibiotics, medical procedures will become ever more difficult. The World Health Organisation has stated that standard procedures such as “organ transplantation, cancer chemotherapy, diabetes management and major surgery (for example, caesarean sections or hip replacements) become very high-risk. In addition to common diseases such as pneumonia and chest infections could become extremely lethal once again. Such an eventuality would increase the rates of mortality, increase the average length of stay within a hospital, and dramatically and adversely impact the economic standing within nations.
The first major problem with antibiotic resistance is the obvious one. Antibiotics, as a medicine, will cease to work. This means that simple bacterial infections will no longer have a cure. Currently, over two million people are infected a year in the United States with bacteria that has gained antibiotic resistance. (Cdc.gov, 2017). And out of these, up to, and perhaps even over, twenty-three thousand die. This is just the beginning, whilst our widespread ability to use antibiotics is mainly intact. However as the effect of AMR becomes ever so more widespread and prevalent, the number of deaths will inevitably rise.
[Figure 1.4] (Graph showing the potential and estimated rise of deaths from antimicrobial resistant infections, compared to the rate of deaths from other causes of death or death causing incidents) (Business Insider UK, 2017)
The above graph shows the estimated increase in deaths from antimicrobial resistance, compared to the increase in deaths from cancer and other diseases/accidents. The scale of the threat from antimicrobial resistance can be truly recognised when the total level of deaths from Cancer will be below the number from antimicrobial resistance. At a total of 10 million deaths, this will almost represent a total of 1 in 3 deaths, and the worst affected will be infants and the elderly. In years gone by, prior to the age of antibiotics, simple scratches and throat infections could and would regularly lead to death. Of course, this was reversed with the invention of antibiotics, however, with their ineffectiveness being slowly actualised, the reverse will be a reality. People will die from a minor cut or scratch if we cannot deal with the problem.
The economic cost of these ten million deaths per year from antibiotic resistance is expected to exceed £66 Trillion. This figure is greater than the current world economy. (World Bank,2013). The impact will be most prevalent on the poor, increasing levels of poverty, increasing global tensions as countries without any major medical complications will become increasingly at risk of high mortality rates, conflict and extreme poverty.
Section 2 – An outline of the Solutions to Antimicrobial Resistance
3.1 – In vitro meat
The rise of lab-grown meat could herald major results in reducing the level of antimicrobial resistance seen today. Evidently as discussed above, intensive farming is a major cause of antibiotic resistance, and as a result, the ability to manufacture meat in a laboratory, with no need to use antibiotics, and no risk henceforth of the antibiotics leaking into the surrounding environments would lead a major way to lower the levels of AMR. Lab-grown meat is the process of culturing meat cells taken from animals, and causing them to multiply using a solution of nutrients and the like. The cost of lab-grown meat has dropped a staggering 30,000 times in less than 4 years and is currently produced at a cost of 3 to 4 times the amount of regular reared meat. By logical extension, one could assume that this price could drop further, and perhaps even undercut the cost of reared meat. (NextBigFuture, 2017). In addition, the general practice of lab-grown meat, options such as veganism and vegetarianism can go a long way to reducing the use of antibiotics in intensive farming. With every drop in the consumption of meat, the need to use antibiotics decreases.
From an evaluative perspective, the advent of lab-grown meat as a readily available commodity, and the widespread increase and adoption of veganism and vegetarianism will go a long way to tackling one of the major contributing factors to antibiotic resistance in bacteria. This is one of the key pillars of the problem, and eliminating it as a factor would take a lot of strain off of the general system and allow a more lax approach by global governments. Government incentive and private investment into the technology behind lab-grown meat, to ensure its profitability, and a general PR campaign to tackle the stigma associated with its consumption would be the last few steps necessary to enact this solution. It is something estimated to happen within the next few decades, if not even this one (ABC News, 2017).
3.2 – Government spending on research
In the UK there is a 5-year antimicrobial resistance strategy to help prevent the rise of AMR. It has three strategic aims, and they are to:
– Improve the knowledge and understanding of antimicrobial resistance
– Conserve and steward the effectiveness of existing treatments
– Stimulate the development of new antibiotics, diagnostics and novel therapies
These are mostly aimed at research, with the UK government and other international bodies have been spending around £276bn on the development of new antibiotics and general research. (University of Birmingham, 2017) (Gov.uk, 2013). However this spending doesn’t go far enough, there have been global calls for a new $2bn research fund, and increasing calls for the UK government to increase its own levels of funding following an exit from the European Union. (BBC News, 2017).
In reality, government spending on research of new antibiotics will only go part the way to solving the problem, perhaps if successful, it will give us a longer length of time in order to tackle the process of AMR. Improving the knowledge and understanding could play a crucial role in developing an effective strategy to combat the problems of AMR, including ensuring that doctors diagnose the correct illness, provide antibiotics only where necessary, and use the correct antibiotics when a patient is sick, rather than plastering them with ineffective or antibiotics of last resort. Additionally, government spending into the advertisement of this problem could go a long way to raise public awareness, with factors such as public misuse of antibiotics contributing significantly, and education within schools and colleges playing a big role in creating a generation of people who do not abuse antibiotics.
With these areas looked into, the slowing of antibiotic resistance, the creation of new antibiotics and the education of the general population as to the problems and to the easy solutions could help. However it is much like global warming, ensuring that many individuals contribute for the wider good is relatively difficult, so it almost always comes to government regulation in order to protect us from the problems we collectively create.
Research could also go a long way to tackle some of the causes of antimicrobial resistance. For example there are some drugs which have been shown to inhibit the functioning of enzymes or efflux pumps. (Chemistry LibreTexts, 2017) (Askoura et al., 2011). Combining such drugs with antibiotics could far further their usefulness, ensuring that the processes of enzymatic modification or efflux were prevented. This is an area where further research must be done, as we may have the drugs available to us now, but we just don’t know it.
3.3 – Government Regulation
This last topic will cover three areas and provide a brief conclusion into the solutions available to us. The first topic will be governmental environmental regulation, the second will be within the medical industry, and the last looking at how global governments could cooperate to legislate against and regulate against rising antimicrobial resistance.
Within the UK, it would be beneficial for the government to tighten its environmental regulations in regards to the manufacture of antibiotics, the general use of them in medicine, and the use of them within livestock.
Firstly, as discussed prior in this report, it is common for doctors to overprescribe antibiotics. One method of government regulation could be to prevent the use of antibiotics in cases which they aren’t a necessity to ensure survival. If one person has a cold, but they are fighting fit and their immune system is up to shape to cure the disease, there is no need for antibiotics. Doctors shouldn’t prescribe antibiotics to those which are more than capable of having their immune system fight off the disease, because the use of antibiotics contributes to a global crisis, compared to, on the other hand, a handful of people having to deal with a cold for a slightly longer amount of time. This system would not only help prevent AMR, but it would also prevent the misdiagnosis of antibiotics on those who were actually infected with viral infections, to which antibiotics would have no effect. Additionally, greater regulation as to the private sale of antibiotics. This would have to affect medical manufacturers and could include moving to drugs providers who do not sell their antibiotics for individual private consumption.
Another thing necessary within the medical industry, is better regulation on which antibiotics can be used and when, those capable of treating the general populace should be used more leniently, and a few strains of antibiotics should be kept under complete lock and key, including no use in the agricultural industry, and no use in general medical practice. Only in the most extreme of cases.
Within the livestock industry, it is necessary for the government to regulate the use of antibiotics to an extreme degree. Including contamination regulations and regular tests on wastewater and water runoff from farms which use antibiotics, the regulation of which antibiotics can be used, and other such regulations. This will likely increase the price of farming, so to counter the problem, the government could either lower rates of taxation/subsidise the cost of farming in the UK to a greater extent, or on the contrary, could set up protectionist measures to ensure that within the UK, our farmers can compete. The prior mechanisms would be more profitable in the long run, and hopefully, as discussed earlier, lab-grown meat will take over from the farming industry as the main source of meat production in the future.
On a global scale more must be done to prevent AMR. What is currently happening in China and other developing nations is rapidly increasing rates of antibiotic resistance occurring, and the residents of these countries will feel the greatest impact. Countries must come together internationally to prevent the sale and misuse of antibiotics, they must work within an alliance to ensure that companies are properly regulated and not polluting the landscape with antibiotics and superbugs. We must work with airline companies to ensure that planes and methods of global transport have better hygiene mechanisms, and places such as airports are kept as sterile environments for bacteria. These are the main points of international spread contagion.
Section 4 – Conclusion
4.1 – The Impact
To conclude on the issue of the impact would be a misnomer of sorts. If left untreated, the number of deaths per annum could exceed cancer, treatments such as basic surgery and blood transfusions would be impossible, and the smallest of scratches could cause death. But this is the worst case scenario. This is what would happen if we do not act to tackle the problem.
In all reality this is unlikely, action is being taken more prevalently and at a greater pace than ever before. The potential problems have not only been outlined, but they have also gained the attention of the scientific community, the press, and now even the politicians.
With proper research, the effects of AMR can be slowed down, we can all work to lower the rates and this would lessen the impact. In reality, the deaths will likely be nowhere near as high, and people will be able to continue with their medical treatments like before. However there is still the risk, that our attempts to subvert the causes of anti-microbial resistance fail, and in this situation, the effect on human life would be catastrophic, it could cause mass poverty, conflict, slow down economic growth.
4.2 – The cure
Several mitigating factors will come into play over this debate. With many factors, there is not one simple cure. It will take an assorted effort from across the board to prevent AMR. With regulation within the farming industry, regulation within the medical sphere, better research and funding into education and new medicines, and a global effort to prevent the misuse of antibiotics we can solve this problem, but action needs to be taken. As a result of this report, individuals should be more aware of the dangers of AMR, and of the scientific mechanisms and societal causes. And as a result, pressure should be put to all parliamentarians in order to help solve this problem; it is the government which needs to act, and more can be done on their part.
A final word shall be this: for us to secure our own certainty for tomorrow, we must act today. Influencing change can be as simple as signing a petition, or writing a letter, and our own Members of Parliament have far greater a sway and influence than most people know. To save the lives of millions, all it could take is a letter from all those which read this report.
Bibliography available on request.