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Charlie Vickers, F1000, discusses the everyday use of antibiotics, the growing problem of antibacterial resistance and the research being done to help combat this problem.

Of agricultural importance…

Almost everyone knows the importance of antibiotics, referred to as antibacterials in this article to avoid confusion, for a range of different uses. However, many people are unaware of just how common their use is, in many aspects of everyday life.

For example, they are most frequently used in agriculture and although this has been outlawed in some countries, in many other parts of the world it is commonplace. In these cases, the antibacterials are often not just given when they are needed, but given continuously, to encourage animal growth.

This is a huge problem, as the bacteria can be zoonotic (diseases which can spread between animals and humans) and in many countries humans still live in close proximity to their animals. Three excellent examples are shown here, in a WHO funded article by Webb et al. They outline the usage, resistance and evidence for transmission for streptothricins, glycopeptides, and colistin.

Looking at just one of these in more detail, colistin, also known as Polymyxin E, is considered an “agent of last resort”, being used in treatments when all other antibacterials fail. It was discovered in the 40s and isolated in the 50s, but due to its side effects was not used commonly in humans. However, as Webb et al. discuss, its use in agriculture is common, if not hard to measure, leading to some gaps in the data.

This is complicated by its different legal status around the world, such as it being legal to use in chickens in the USA since 1998, or it being illegal for agricultural use in Canada, except for certain loopholes, which many farmers are believed to exploit. Further to this, China is almost certainly the world’s biggest colistin producer and user, although its use to promote growth in animals has now been banned.

As is a recurring theme with colistin, there are gaps in the data regarding resistance levels in agriculture, although reports of colistin-resistant bacteria are becoming more common and geographically spread, which may limit its use as a last resort antibacterial in humans.

Of surgical importance….

Other than their uses in agriculture, antibacterials also play an important role in many aspects of modern medicine. Dr Katsumi Shigemura and colleagues recently highlight that almost all surgery may require the use of antibacterials, and they are also crucial in many cancer treatments. Here they describe the latest version of their study protocol for prophylactic antibacterial administration during benign prostate hyperplasia therapy, following a round of revisions suggested by Seung-Ju Lee and Florian Wagenlehner.  

Previously, the most effective way to treat the prostate hyperplasia such as those described in the protocol was using invasive surgery which, according to NICE,  has a high morbidity. This led to the development of a minimally-invasive method, Holmium laser resection of the prostate (HoLRP), which should in theory, have lower morbidity. This uses a laser as a “precise cutting instrument” in order to remove sections of the prostate.

Despite it being non-invasive Shigemura et al. report that there are still high levels of urinary tract infections following the procedure (although not as high as following invasive surgery). In order to combat this, the authors propose a trial to determine the optimal duration of antibacterial use given prophylactically (when a drug is used to prevent infection as opposed to treat one after the infection has occurred). According to Florian Wagenlehner, one of the reviewers for this article, the study protocol is “well described and set up, including the important in- and exclusion criteria”.

Understanding the problem and the next steps…

One way of showcasing the widespread nature of the problem of antibacterial resistance is to demonstrate how many of the bacteria we encounter in our everyday lives possess the genes that cause them to be resistant.

A few years ago, Millman et al. tested retail poultry for E.coli which were resistant to Ampicillin, a widely prescribed antibacterial, alongside some other antibacterials. They found that in Kosher meat, up to 62% of the samples they tested contained bacteria which was resistant to Ampicillin, despite Kosher meat preparation being historically believed to be a safer food preparation method.

Surprisingly, chicken samples which had been raised without antibacterials did not always show the lowest levels of resistance. Table 2 of the article shows the results in the most succinct way, displaying the antibacterial-resistance profile for the differing preparation methods.

In a similar 2018 study, it showed that the type of meat was also a factor in the levels of antibacterial resistant bacteria being found, although the results were not statistically significant. It may therefore be possible that there are a wide number of factors at play, causing different resistance levels in different samples.  

Pattern learning

One potentially important way of combating antimicrobial resistance is to use machine learning, the process by which computers become better at a task over time by learning from both correct and incorrect responses. Despite requiring a human input initially, once a computer has learnt the patterns, it will be much faster than doing this work manually.

It may be possible that this will allow us to predict the antibacterials that will be most effective against a given bacterium – for example, if it were causing an infection and was resistant to the usual antibiotics as shown by McDermott et al.

Many antibacterials work by changing the important balance inside the cell of a bacterium, known as the homeostasis. One way for a bacterium to be resistant to an antibacterial molecule, can be through pumping the antibacterial molecule outside of its cell wall, therefore making the antibacterial ineffective. This sometimes occurs via proteins known as efflux pumps, which can be capable of removing a number of different antibacterials. Different types of pumps are found in the cell membranes throughout all life forms, but it is the ubiquitous nature of some of these pumps which is so rare.

Using the power of machine learning, they applied this knowledge to be tested on environmental bacteria, in order to detect whether they were resistant to a number of different antibacterials (aka mulitdrug resistant – MDR) or not. However, as the variety between environmental bacteria is so great this was hard to implement, although they believed they may have detected a number of bacteria which were MDR. 

With an increase in research and more powerful computers, this may be implemented in the future, reducing the number of antibacterials which are prescribed to treat an infection which they have no efficacy against. For example, if a patient undergoing the removal of the prostate tumour procedure described by Shigemura et al. was to contract an infection, this would allow them to be treated with the best antibacterial for the bacteria responsible.

Stemming the tide

With such a range of uses, from the farm to the treatment table, antibacterial resistance is becoming more common. We can put this down to survival of the fittest evolution and the frequency is  evident when looking at this figure in a 2015 article by Alan Johnson.

To combat this worsening problem, it may seem that turning to innovative, flexible methods, such as those described by Shigemura, McDermott and their colleagues, is the only way to stem the tide against resistance.

Want to read more on antibiotics and antibacterials? Then browse through our content on F1000Research for more articles covering this subject area, as well as Faculty Reviews and Posters.