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The problem with antimicrobial resistance

by Arabel Luscombe Published on 4th Nov 2015

by Arabel Luscombe Published on 4th November 2015

A brief glance at some of the medical discoveries that have been made in recent years is enough to leave one impressed at the state of modern medicine. Whether it’s bionic organs or stem cell research, medical progress seems to be advancing at a staggering rate.

However, at the same time, many of the basic achievements of modern medicine are under threat from a much more banal, and relatively under-reported, phenomenon – namely that of antimicrobial resistance.

Antibiotic Resistance

The most well-known – and perhaps most troubling – form of antimicrobial resistance is antibiotic resistance, i.e. the tendency of bacteria to become resistant to treatment (although viruses and fungi can also develop resistance to medicine). Use of antibiotics creates a type of selective pressure in bacteria populations, where those bacteria with little resistance die, while those with resistance survive and multiply. Over time this can lead to the development of disease strains that are completely impervious to existing antibiotics. This risk is inherent to the use of antibiotics, and scientists have been aware of it for a long time – indeed, Alexander Fleming warned of the dangers arising from antimicrobial resistance in 1945 while accepting his Nobel Prize for the discovery of penicillin. It did not take long for his fears to be confirmed and penicillin resistance to become relatively widespread.  

For quite a while, however, this was not seen as an urgent problem, as scientists kept discovering new antibiotics, thereby compensating for growing resistance to existing drugs. This was the so-called “golden age” of antibiotics, which lasted until the 1970s. But then the development of new antibiotics dried up – the last completely new class of antibiotics to be licensed was discovered in 1987.

The majority of existing antibiotics were developed by extracting microbes from soil, but at a certain point this appeared not to work anymore, as it was impossible to grow most soil microbes in normal laboratory conditions. Moreover, pharmaceutical companies had little interest in developing new antibiotics, as the potential for profit is very low in comparison to other types of medicine, in particular those used to treat long-term, chronic diseases (antibiotics, by contrast, are only taken for a short period of time). One of the last major pharmaceutical companies continuing to research new antibiotics was Pfizer, which ceased its main research operations in 2011, quoting financial reasons.

Antibiotic Overuse

The problem is exacerbated by persistent overuse of antibiotics. According to the EU's Joint Programming Initiative on Antimicrobial Resistance, 70% of antibiotics are prescribed incorrectly. For example, antibiotics may be prescribed to treat flu-like symptoms that are actually caused by a virus, against which antibiotics are completely useless. This is partly related to patient expectations that they receive some type of prescription when they go to the doctor, but it is also the result of inadequate or lengthy diagnostic procedures – if doctors don't know how to diagnose a patient, or don't have time to wait for the results of the diagnostic test, they may rely on the use of broad-spectrum antibiotics. Additionally, in some countries it is very easy to buy antibiotics without a prescription, which massively increases the risk that they will be used incorrectly.

Moreover, antibiotics are not only used on humans – in fact, it has been estimated that around 70% of antibiotics sold in the US are given to farm animals. These are not only administered on a large scale to prevent occurrence of disease (i.e. before the animals actually get sick), but are also used to encourage growth. Antimicrobial resistance in animals has therefore developed into a major problem, and – while animal diseases are different to human ones – it is possible for drug-resistant animal infections to be passed on to humans. For example, several outbreaks of multi-drug resistant Salmonella in recent years have been traced back to consumption of beef and poultry products.

As a result of these factors, antimicrobial resistance has already developed to a point where it is causing major harm. A large number of drug-resistant diseases have become widespread, including strains of tuberculosis and gonorrhoea, as well as the hospital “superbug” Meticillin-resistant Staphylococcus Aureus (MRSA). According to figures from the US Centres for Disease Control and Prevention, more than 20,000 people die in America every year as the result of untreatable infections.

While there are signs that MRSA has been brought under much better control in recent years, the same period has seen an increasing trend towards multi-drug resistance in other types of bacteria, in particular Escherichia coli (a major cause of urinary tract infections) and Klebsiella pneumoniae (which can infect the urinary tract, the respiratory tract and the bloodstream). In regard to the latter, a troubling development has been the recent growth of resistance to the carbapenem class of antibiotics, drugs that are often used as the last line of defence against multi-drug resistant bacteria.

Prognoses for the future are even more worrying. According to the UK government's Review on Antimicrobial Resistance, 10 million people could die annually by 2050 as the result of untreatable infections. If things get worse, we could return to conditions in which minor, everyday infections can prove deadly. This would have massive implications for medical practice; surgery, for example, would become much more risky. Vital surgical procedures that we take for granted, such as joint replacements or organ transplants, could become untenable, as the risk of post-surgery infection would be too high. The use of chemotherapy, which suppresses the human immune system, also relies on the application of antibiotics to prevent infection and would be much more dangerous if these no longer worked.

In view of its potential to undermine so many of modern medicine's achievements, antimicrobial resistance has been described by Sally Davies, England's Chief Medical Officer, as a “catastrophic” threat. Some observers have compared it to climate change, in the sense that it is an enormous problem with huge consequences for the entire world, yet very little is actually being done about it.

Research on new antibiotics

Partly this is related to funding issues. As mentioned above, there is very little financial incentive for pharmaceutical companies to invest in the development of new antibiotics. For this reason, many people see hope resting primarily on government funded research in university departments, or call for measures to incentivise research in the private sector. There are some indications that national governments are beginning to take the problem more seriously – in 2012 the UK government launched a five year action plan on antimicrobial resistance, and the White House issued a similar plan early this year. However, actual funding levels have been very low. Of the $142.5bn spent by the US National Institutes of Health on research between 2010 and 2014, for example, only $1.7 was designated for antimicrobial resistance. In the UK, £14bn was made available for research on bacteriology between 2008 and 2013, but only £95m of this was spent on the search for new antibiotics.

Nonetheless, there are signs that some progress is being made. At the beginning of 2015, a group of researchers from Northeastern University in Boston, Massachusetts announced the discovery of an entirely new form of antibiotic, teixobactin. It had been thought that soil offered no further possibilities to discover new antibiotics, as most soil microbes cannot grow in laboratory conditions, but the researchers managed to do so by using an innovative new way of encouraging growth. This is very promising, as it suggests it may be possible to develop many more antibiotics from soil. Moreover, teixobactin attacks bacteria in a different way to most antibiotics, making it less prone to the development of resistance. The researchers who discovered it think it may take at least 30 years for significant resistance to appear. As of yet, however, teixobactin has not been licensed for clinical use, and it will take some time before even the first clinical trials are possible.

Other research areas

Besides development of new antibiotics, there are a number of other research areas that may provide ways to deal with the problem. One of these involves the use of bacteriophages, viruses that infect and kill bacteria and which were already used as a form of treatment in the Soviet Union. In contrast to antibiotics, phages only attack specific bacteria, meaning they leave good bacteria intact. However, the specific nature of their attack represents an obstacle, as doctors may not know which exact bacterial strains are causing an infection and would have to treat patients with multiple phages. Supplies of phages would need to be regularly updated, and each new phage would have to pass regulatory tests. At the current moment phage therapy is only readily available in certain countries, but there have been several relevant clinical trials in recent years, and the use of phages to prevent Listeria contamination in meat products has been approved in the US since 2006.

Another potential alternative to traditional antibiotics relates to the use of antimicrobial peptides, short chains of amino acids that are part of the natural immune systems of all living creatures. Peptides are capable of killing bacteria (those isolated from amphibians and reptiles are particularly effective) and research is currently ongoing on the possibility of isolating and modifying them for clinical use. Although it is possible that bacteria would develop resistance against peptides, some researchers argue that this would only occur very slowly, as bacteria would find it difficult to adjust to their mode of attack. On the other hand, as the human body naturally uses peptides to fight infection, there exists concern that any resistance that does arise would compromise natural defence mechanisms, i.e. those bacteria with resistance to clinically applied peptides might also be resistant to those produced by the immune system.

It is also worth mentioning current research that focuses on the way in which bacteria communicate with each other. Bacteria use chemical signals to alert each other to their presence, meaning they can wait until they have reached a critical mass before attacking a human cell. This process is known as quorum sensing and makes their attack far more virulent than if they would act individually. Researchers are therefore working on mechanisms that interfere with this process, in the hope this would allow the immune system to react while it still has a chance of success.

In addition to those research areas mentioned above, other potential alternatives include the use of predatory bacteria that attack their fellow microbes, the application of metal nanoparticles (although the possibility of metals accumulating in the body and poisoning it significantly limit this approach) and ways of encouraging the beneficial bacteria that live in the human gut. A more traditional strategy would be to focus on development of new vaccines, although – as with all the other alternatives mentioned so far – it is controversial to what extent these could replace antibiotics, and many people only see these new therapeutic strategies as complementary to traditional antibiotics. In all cases, there is a need for much more research before any real certainty can be achieved.

In the meantime, the British and American action plans on antimicrobial resistance both include measures to reduce overuse of antibiotics. It is hoped that this can be partly achieved by the development of new and better diagnostic tools, as well as wider use of existing rapid diagnostic tests. The use of whole genome sequencing, for example, could provide much faster results than those that are currently in widespread use. Other measures foreseen to reduce overuse include better education of doctors and tighter control of prescription practices. Improved hospital hygiene could also limit the spread of infection and thereby the need to use antibiotics. However, while measures to improve hygiene and reduce misuse of antibiotics are clearly very sensible, they can at best slow down the pace  at which resistance develops. Research on new antibiotics and alternatives is therefore imperative.