Yet another reason to hate mosquitoes

Living in the UK I am often sucked into writing my blogs based only on news stories occurring here. This time I have decided to change that formula and focus on a story that has hit the headlines the other side of the pond in the United States. The headlines are surrounding the increasing spread of West Nile virus. As of 14^th August there had been 696 cases and 26 deaths. Come the start of September these numbers had increased to 1993 cases and 87 deaths, then as of the 9^th September (only a week later) the numbers had reached 2636 cases and 118 deaths. This outbreak is the largest in the US since 2003 in terms of the number infected, and also has the highest proportion of the most serious form of infection since the virus was first discovered in the US in 1999. West Nile virus is not necessarily something many people know about beyond the headlines, so as usual, this has spurred me into writing a blog giving some detail on the virus itself.

Culex mosquito

The first thing to point out with this virus is that it is classed as an arbovirus. This is the fancy word for a virus that is transmitted by an arthropod vector, much like malaria for example (though that is not caused by a virus). West Nile virus (WNV) is transmitted by a species of mosquito known as Culex, while malaria is carried by a different species known as Anopheles. WNV is the most widely distributed of all the arboviruses, seen in every continent, except Antarctica. It is important to know that the virus is spread by mosquitoes as this plays a major role in the epidemiology of the virus, as will hopefully become apparent in this blog.

Along with mosquitoes (and obviously humans) the virus is found in birds, and it is in fact these animals that are the natural reservoir for the virus, not humans. Evidence for this comes from the fact that the virus replicates best when in a species with a high body temperature. Most birds have a natural body temperature of around 41^OC, which is ideal for the replication of WNV. Humans on the other hand have a temperature around 37^OC, which has been shown to limit the replicative ability of the virus, indicating humans are merely an incidental host. The virus is best adapted to replicate in birds, but can use humans if needs be.

Usually Culex mosquitoes feed on birds that are carrying the virus and spread it amongst the bird population. However, in very hot and dry weather this changes. Under these climactic conditions it becomes harder for plants to survive. Plant death has an impact on the population levels of the insects that feed on them. Since many birds feed on insects, if there are less insects the population number of birds will also suffer. If there are less birds to feed on the mosquitoes will move on to a less favoured, but more accessible meal; humans. So when hot and dry weather is seen for prolonged periods of time there is an increase in the level of mosquitoes feeding on humans, raising the chance for spread of WNV in the human population. This is exactly what is happening in America right now, some of the worst affected areas (such as Texas, where roughly 40% of cases have occurred) are currently in drought which very high temperatures (even for summer).

West Nile virus particles

 WNV in humans is often an asymptomatic infection (partly down to the fact that we are only an incidental host), with roughly 80% of people who get the virus not developing any symptoms. Close to 20% of people infected will develop non-neuroinvasive disease that is characterised by fever, aches, vomiting etc. While West Nile fever is nasty for a few weeks, people with this form of infection will usually recover and be completely healthy. However, around 1 in 150 people infected by the virus will develop the most severe, neuroinvasive, form of the disease, which is characterised by virus entering the brain. This form of WNV infection is responsible for most fatalities.

The current outbreak in America has so far been characterised by a much higher percentage of patients showing neuroinvasive infection, though it is not clear why. These patients develop encephalitis (swelling of the brain) and can develop other complications such as meningitis. The fact that the virus causes swelling of the brain adds an interesting characteristic to the infection. Young children have a suppler skull than adults. If a child develops encephalitis from neuroinvasive WNV infection there is much more give in the skull meaning they are less likely to suffer severe complications. People over the age of 55 are at this highest risk of severe complications from neuroinvasive WNV due to their skull being firm (the brain has no room in which to swell).

Currently there is no vaccine and no specific antiviral drugs against WNV. Weirdly the main form of treatment that is given for WNV infection is steroids. This is weird in the sense that steroids suppress a patient’s immune system. While suppressing the immune system is clearly not good in terms of fighting off a viral infection, inflammation is also controlled by the immune system. Therefore, if the system is suppressed there will be less inflammation, meaning the swelling of the brain seen in neuroinvasive infection will not occur (or will at least be suppressed). Over time the patients on steroid treatment will be able to remove the virus due to the fact that it does not replicate particularly well in humans (as I mentioned previously). However, it is likely that this recovery will be a drawn out process due to the compromised immune system (the patients will suffer the fever, aches, vomiting etc for longer). This is clearly not a particularly good strategy to deal with the virus, and clearly more work needs to be done in the field. Hopefully the current outbreak in the US will help keep funding up in the WNV area and allow for the development of an effective vaccine, or at least specific antiviral drugs.

The current outbreak of WNV in the USA has the second highest number of cases seen since the virus was first introduced to the country in 1999. The outbreak is also the most severe in terms of a high percentage of patients developing neuroinvasive infection. There has recently been a huge jump in the number of confirmed cases; back in mid-August there were 693 cases, come the start of September there were 1993 cases and a week later there were 2636 cases. These figures imply that the virus is spreading rapidly, however this is slightly misleading, as there is a delay between patients being tested and the results being received. Another contributing factor to the slightly misleading figures is that more and more people are being tested due to the current hype around the outbreak. In a normal year it is likely that many people will develop non-neuroinvasive WNV but will pass it off as just a bout of flu (fever, aches, vomiting etc), so will not be tested (and therefore recorded). Since WNV is in the headlines, more people are being tested, meaning the numbers are slightly distorted. I’m not denying that this outbreak is serious; I’m just pointing out a small fact about these kinds of statistics that is often overlooked. Fortunately, in some respects, the virus is completely reliant on the mosquitoes, therefore when summer ends and the mosquito numbers drop the epidemic will end. There is an end point to this epidemic, hopefully sooner rather than later.

Watch this spot

On 24^th August statistics were released showing that the number of measles cases in the UK have almost doubled in the first half of 2012, as compared to the first half of 2011. Figures from the Health Protection Agency show that in the first six months of the year the number of cases have risen from 497 to 964. This large increase can be partly attributed to two significant outbreaks in Merseyside and Sussex. Interestingly, even though there have been outbreaks and an overall rise in the number of cases, the uptake of the MMR vaccine (protecting against measles, mumps and rubella) is at a very high level, with 93% of patients receiving the first dose and 87% receiving the second dose. Due to this story making the headlines and the fact that there is a lot of interesting stuff about the measles virus I thought I would write a blog on it all.

Measles vaccination

First and foremost I’d like to make one thing clear, there is no proven link between MMR and the development of autism. This is an old story but it’s hard to talk about measles without talking about the MMR debacle. Back in 1998 a study, conducted by Andrew Wakefield, was published in The Lancet medical journal demonstrating a link between receiving the MMR vaccine and developing autism in children. This study ignited a debate over the safety of the vaccine and saw the uptake rates fall to the lowest level since the introduction of the triple vaccine back in 1988. However, controversy reigned over the study and numerous other studies were conducted using millions of children. All of these ensuing studies failed to find any evidence of a link between MMR and autism. Over time it came to light that Wakefield had conducted the research with multiple undeclared conflicts of interest including funding from a law firm preparing a legal case against the MMR vaccine (it was reported that he personally received more than £400,000 from the firm). The Lancet paper was eventually retracted and Wakefield found guilty of serious professional misconduct, ending with him being stuck off the Medical Register in the UK. Suffice it to say, there is no clear evidence that the MMR vaccine has a link to the development of autism and the vaccine has been proven to be safe and effective at preventing infection from all three diseases.

Now that the controversy is out of the way, we can move on to the even more interesting biological aspects of the virus. The first thing I would like to look at is what the virus gets up to when it causes disease. The measles virus is spread by the aerosol route, much like influenza. A patient may sneeze or cough droplets carrying the virus particles which then move on (through the air or via surfaces) to infect a new individual. Due to the route of transmission the virus will first enter into an individual’s respiratory tract and make its way to the lungs. In the lungs the virus is able to infect resident immune cells; these are cells that are naturally housed in the lungs ready to pounce on any invading organism. The virus uses the SLAM (also known as CD150) receptors to enter the cells. Once these cells are infected they will leave the lungs and head to the lymph nodes. At this point the virus will replicate and start to infect more cells causing swelling of the nodes. Eventually the virus will leave the lymph nodes to infect epithelial cells around the body (these are cells that make up all the surfaces of the body: the skin, the lining of the gut, the lining of the lungs and so on). When the virus makes it to skin cells it will enter and cause the famous rash seen in measles patients. This whole process, from lungs, to lymph nodes, to skin, takes around 10-14 days (the incubation period of the virus).

Classical measles rash

All that is left for the virus to do now is to transmit to a new host, meaning it needs to get back to the lungs. For a long time it was unclear how this was achieved. The SLAM receptor used when the virus enters had been known about for a long time, but there are no SLAM receptors that would allow the virus to get back to the lungs, the entrance was known, but the exit was hidden. It wasn’t until late last year when the exit door was found to be a protein known as Nectin 4. This protein is only found on one side of the cell, known as the basolateral side (the side which is in contact with the blood system). It would be impossible for the virus to use Nectin 4 upon entry through the lungs, but once already in the blood system it has easy access to Nectin 4, allowing the virus to enter the lung cells and spread in a cough or a sneeze. Nectin 4 is also the protein that allows the virus to get into skin cells, so is responsible for the classical rash. It might just be me who thinks this, but the fact that this virus has evolved to use two completely different receptors, on two completely different cell types, for the processes of entry and exit, is very cool!

The next aspect of the virus I’d like to look at is the paradoxical immuno-suppression that is seen following infection. A patient who contracts measles tends to mount a very good immune response against the virus and will, over time kill it (the normal situation with most infections). However, for a couple of weeks to a month after the virus has been removed (and the disease cleared) the patient has a weakened immune system. The measles virus in itself is not a particularly dangerous virus; the real danger comes from the weakened immune system that follows infection and makes the patient particularly susceptible to secondary infections. Most deaths associated with measles are caused by pneumonia or diarrhoea, both of which are secondary infections. The reasons behind this immuno-suppression are not fully understood. It has been seen that even after the virus has been cleared from the body parts of the viral genome can still be detected in the blood for weeks after infection and we also know that measles targets immune cells through the SLAM receptor (as I mentioned above). It is possible that both of these factors may contribute to the measles-associated immuno-suppression that can cause complications to the viral disease (the genome could distract the immune system so it is only focused on measles and nothing else, and targeting immune cells may kill them).

Electron microscope image of measles virus

The final aspect of the measles virus I’d like to share with you is its infectivity. Measles is one of the most infective diseases that we know of. Infectivity is measured by a value known as R₀. This value is the number of people who will be infected from an individual carrying the disease, through the course of the infection. So an R₀ of 3 means a patient with a disease will, on average, infect 3 other people. To give some context to this, HIV has an R₀ of 2-5, seasonal influenza has an R₀ of 2-3 while smallpox and polio both have a R₀ value of 5-7.  Even with a low R₀ HIV has managed to infect nearly 34 million people and until its eradication, smallpox was an incredibly feared disease; even seemingly small values can wreak havoc. Measles has a R_o of a whopping 14-18! So for every person who carries the measles virus, they could (were it not for the vaccine) infect between 14 and 18 people. A scary fact when compared to the other viruses.

Two apt demonstrations of the infectivity of measles virus have been seen in Indiana (USA). The first of these was in 2005 when an outbreak was traced to an unvaccinated girl who had recently travelled to Romania. She came back harbouring the virus, but yet to display any symptoms (most likely while the virus was replicating in her lymph nodes). She then proceeded to go to a church gathering as the first symptoms (cough, sneezing etc) appeared. At this gathering there were 500 people, of these 50 were unvaccinated against measles and of these unvaccinated people 16 were infected by the one girl carrying the virus (R₀ between 14 and 18 remember). Another outbreak occurred in Indiana in February this year following Super Bowl XLVI. Roughly 17 people were diagnosed with measles following the game. Although the person responsible has not been identified as with the 2005 outbreak, it is again likely that all 17 cases stemmed from one infected individual.

I think measles is a fascinating virus. Unlike many other viruses it is highly evolved to target two different receptors and therefore two completely different cell types. On its way in, the virus uses SLAM receptors found on immune cells, then to escape and pass on to new people it uses the Nectin 4 receptor of epithelial cells. The virus is generally well controlled by our immune system, but once cleared it leaves the nasty parting gift of prolonged immuno-suppression, making a patient highly susceptible to secondary infections, which are responsible for many of the complications seen with measles infections. Measles is also one of the most infectious viruses we know about. Fortunately we have a very effective vaccine in the form of the trivalent MMR jab. Due to how highly infectious measles is it is essential to have very high coverage of the vaccine. The World Health Organisation has set a target of 95% coverage, a target which, here in the UK, we are very close to achieving, with 93% coverage for the first jab. However, even falling slightly short, and having a lower uptake for the second jab (only 87%) gives the virus enough opportunity to spread and cause outbreaks as have been seen during the first half of 2012. Measles is a preventable disease, and is very likely to be the next target for eradication, if we ever manage to get rid of polio. The key is to keep on vaccinating!

Her name was Reo and she killed cancer

We live in an ageing population, especially in the developing world. With the huge increase in life expectancy that has been achieved in the previous 100 years, diseases of old age have come to the forefront of medial thinking; none more so than cancer. In the UK alone, roughly 320,500 people were diagnosed with cancer in 2009. I use the UK as an example, as opposed to using a worldwide statistic, since in the developing world a huge proportion of cancer comes from infectious diseases. Cancer causing infectious diseases are much better controlled in the UK and other parts of the developed world, making cancer predominantly a disease associated with age. Cancers related to age form due to mutation of cells caused by so called ‘mutagens,’ such as ultraviolet light (from the sun) or chemicals (eg. in cigarette smoke). Multiple mutations (around 6-7) are needed in order to make a cell cancerous. In order to acquire all of these necessary mutations a cell needs time, which is why cancers can be regarded as a disease of age. The treatment of cancer has dramatically improved in recent times, but we are still without a consistent cure and the treatments which are used are not without some serious side effects. Until a complete cure is found the science world will continue to look for new and improved treatments. To that end, I would like to look at one of the slightly stranger approaches; the deliberate infection of patients with a virus to treat their cancer.

When most people think of viruses the first thought is of disease; viruses such HIV (AIDS), influenza (flu), rhinovirus (colds), and so on, are likely to spring to mind. However the vast majority of viruses on our planet do not cause humans any ailments at all. Many viruses will never come into contact with humans and so never get the chance to cause infection, our immune system keeps many viruses at bay and many viruses do not grow well in human cells; to cite just a few reasons as to why the majority of viruses have little effect on us. This brings me onto reovirus, a double stranded RNA virus which is ubiquitous amongst the human population. Many individuals will carry reovirus in their airways and lungs or gut and be completely healthy; the name reovirus itself eludes to this fact being that 'reo' is an acronym of respiratory, enteric, orphan (with orphan denoting that there was no known diseases when the virus was discovered). Some reovirus strains have now been found to cause an infection but it is characterised only by mild flu-like symptoms which people recover from in a short period of time.

Reovirus

The reason behind the lack of disease caused by reoviruses comes from the fact that they do not grow well in normal human cells; however cancer cells are far from normal. As I’ve mentioned, cancers are caused by mutations in normal cells. A defining characteristic of cancerous cells is their ability to grow and divide much faster than their normal counterparts, a change which is controlled by mutation. One of the most common ways this increase in growth speed is achieved is through mutations to a cellular process known as the Ras pathway. When the Ras pathway is mutated the cell goes into overdrive and will grow and divide much faster than its normal counterparts, making it able to form a mass of cells (a tumour). Interestingly, while reovirus grows poorly in normal cells, it is very good at growing in cells that have a mutation in the Ras pathway (though we do not fully understand why). In cells containing the Ras mutation, any infecting reovirus will grow rapidly and cause the cell to lyse (a fancy word for burst), thus killing the cell. This bursting kills the cancerous cell but leaves normal cells perfectly healthy. The bursting of the cancer cells also has an additional advantage in that it can cause activation of the immune system to attack any remaining cancerous cells. The virus and the immune system are therefore able to work in harmony to attack, and kill, the cancer.

Reovirus is capable of infecting, and killing, any cancerous cell that contains a Ras mutation. Ras mutations occur in around 20-30% of all cancers ranging from breast, to prostate, to brain, and so on. Ras mutations can also be seen at levels of up to 90% in some specific cancers (such as pancreatic), so reovirus has the potential to impact a very large number of cancer cases.

The use of reovirus for the treatment of cancer is not just at the idea stage. Oncolytic Biotech® has been working on their product REOLYSIN® for some time now. The product has entered phase III clinical trials (the final step before becoming licensed) as treatment against head and neck cancer and is in phase II trials for other forms of cancer. So far the results are highly promising, the virus is well tolerated and has, at worst, only causes some mild flu-like symptoms. It may not be long before we see REOLYSIN® hit the hospitals as a treatment against head and neck cancer, and potentially other forms as well.

Recent work has also shown that reovirus treatments can be administered into the blood of patients instead of being directly injected to the cancer as was the case with the original procedure. It was believed that if the virus was given in the blood it would simply be destroyed by the immune system, like many other viruses. Instead, it was found that the virus is capable of becoming a stow-away in red blood cells. The virus can enter red blood cells where it is hidden and protected from the effects of the immune system, it then simply waits inside its little red bus until it reaches the cancer stop, where it alights and begins its attack on the cancer cells. Since it is much easier to inject someone in a blood vessel than directly into a tumour, this finding is likely to make reovirus an even more viable option as an anticancer therapy.

The idea of using a virus to treat disease is something I find truly fascinating. Viruses so often get a bad reputation for the damage they have caused, but through continued scientific research we are starting to find ways to turn these old adversaries to our allies. It may not be long before we see reovirus being prescribed as a treatment against cancer.

Just A Sniff To Prevent Flu

On 25^th July it was announced that the UK are to implement a program of vaccination for children aged 2-17 years old against seasonal influenza. The proposed change won’t come into effect until 2014 and it is believed that it will cost in the region of £100 million a year. There has been much talk about this level of spending with the economy the way it is, so I thought I would write a blog giving some details on the proposal and attempt to convey the benefits of the spending.

Firstly, a little background into flu vaccination. We currently have an annual flu vaccine which is given to ‘at risk’ individuals just before the onset of the flu season (winter). The vaccine contains three different strains of influenza which are predicted to be present during the up and coming flu season. Straight away we hit a slight snag here; the vaccine is made from virus strains which we are expecting to be circulating in the coming months. We need to base the vaccine on ‘guess work’ since it can take as long as six months to produce enough vaccine for everyone who needs it; this is also the reason why we only target ‘at risk’ individuals, we simply can’t make enough for everyone at present. The production of flu vaccine is slow because it relies on growing the virus in eggs, from where it will be collected and made into the vaccine. I say the vaccine is based on ‘guess work’, but this does a huge disservice to the vaccinologists and epidemiologists. The three chosen strains of the virus are picked on the basis of months of surveillance and a lot of data crunching, and the ‘guesses’ that are made regarding which strains to use are rarely incorrect. If the wrong strains are chosen, or the strains circulating change, then it we are likely to see an outbreak.

The current flu vaccine is given to over 65s, pregnant women, chronically ill patients etc. The vaccine is given as an injection and is made of inactivated virus. There are two major categories of classical vaccine, these being inactivated and live-attenuated vaccines (I’ll come back to the latter of these shortly). The inactivated vaccines contain virus particles that are completely inert; they have been ‘killed’ by treatment with chemicals. This version of the flu vaccine is injected into the arm of patients and delivers dead influenza particles which subsequently trigger our immune system to develop a, so called, ‘memory response’ against the flu virus. This memory response means that the next time a live influenza virus (of the same strain as was in the vaccine) enters the patient the immune system will have a very rapid and strong response, so as to completely protect from any severe disease.

Live-attenuated vaccines are slightly different as they do not use killed virus. These vaccines use a weakened (attenuated) form of the virus which is less capable of causing disease. An example of this attenuation is known as cold-adapted virus. To produce this form of a vaccine, virus is grown at temperatures much lower than human body temperature. The virus evolves to grow effectively at these low temperatures. When the virus is then in the human body, at a much higher temperature, it does not grow as well as it usually would. The virus will be cleared by the immune system before it is able to evolve back to growing at human body temperature and provide a protective memory response at the same time. This is just one example of how a live-attenuated virus can be produced, there are many other methods.

Both the inactivated and live-attenuated vaccines have their pros and cons, but the main point is that live-attenuated vaccines tend to give a better level of immunity since they more closely mimic a real infection, but they also carry more risk. The risk with live-attenuated vaccines comes from the possibility of ‘reversion’ whereby the virus mutates back to its normal (wild type) form. If reversion occurs then the vaccine has a chance to cause the very disease it is designed to protect against. We currently use an inactivated virus for the seasonal flu vaccine since there is no chance of reversion, making it safe to give to people who are at the most risk of a severe infection. Children tend to have much stronger immune systems than those classed as ‘at risk.’ It is therefore safer to give children a live-attenuated vaccine since they should be able to fight off the virus before it reverts and, should it revert, they are better able to recover from the disease without any severe complications.

A shot of FluMist

That covers the background, so now we can move onto the proposal of vaccinating all 2-17 year olds here in the UK. The first important point to note about the proposal is that it plans to use a vaccine that is given as a nasal spray, instead of an injection, making it much easier to give en masse (and much less painful). The nasal spray vaccine has been used in the United States since 2003, under the name FluMist, and uses live-attenuated virus.

The next big thing to consider is the reason behind targeting children with this vaccination. Flu is predominantly a disease of the old and the young, however it is much less likely that infection with influenza will cause severe disease in children, so some may ask why bother? There are a lot of reasons to bother. The main reason lies with the concept of herd immunity (which isn’t the easiest thing so bear with me). In an ideal world everyone would be vaccinated against every disease possible. If this was the case, then the virus would never cause any infections (and would die out). However, it is impossible to get 100% coverage of a vaccine in the real world. What is instead attempted is to achieve a level of coverage high enough that everyone is, in effect, protected. Let’s say there are a group of 1 million people. If 90% of these are vaccinated there are only 100,000 of the 1 million who can get the disease. If one of these ‘at risk’ individuals gets infected the chances of them meeting one of the other 99,999 who could get the disease is very slim (99,999 who could get infected against another 900,000 who can’t), making spread unlikely. Those people who haven’t been vaccinated are therefore protected simply because such a high proportion of the population has been. With a high level of coverage there is a good level of herd immunity.

If we vaccinate all children aged 2-17 we reduce the number of people who can become infected and subsequently spread disease. This will help to protect people who are at even greater risk of severe disease, for instance, a child’s grandparents who they may visit while carrying infective virus. If you have read any reports about this new proposal you may have seen the quote that, “even with moderate uptake of 30% it's estimated that this should result in 11,000 fewer hospitalisations and 2,000 fewer deaths each year,” from the Chief medical officer Professor Dame Sally Davies. These estimated figures are based around the concept of herd immunity, as well as the direct effects of vaccinating the children.

Herd immunity is not the only reason to vaccinate children. A child who gets flu will have to take time of school, potentially up to a couple of weeks. This means a parent would have to take time off work. Being at home with a sick child also makes the parent more likely to contract the disease themselves and have to take further time off work. Missing work is clearly not good for the parent, nor is it good for the economy as a whole. I have only used the examples of reduced hospitalisation and reduced time off work, but hopefully already you can see the economic logic behind the proposed move. I’d hate to have been the person to do these sums, but it has been estimated that the approximate £100 million a year cost for the vaccine campaign is cost effective when compared to the other economic benefits it could have.

For the majority of children, influenza is not a killer disease. However, starting in 2014 it is highly likely that we will see a huge campaign to get as many 2-17 year olds vaccinated against the virus as possible. The vaccine will help to reduce the cases of influenza infection in children, which, while rarely fatal, is still fairly nasty and not one you’d want to have if you can avoid it. The campaign will also help to protect those at higher risk of severe influenza by increasing the level of herd immunity. It won’t be a cheap campaign, but the simple fact that it will help prevent many cases of flu will help reduce the costs needed to treat these people, making it cost effective. Away from cost-effectiveness, if you could prevent yourself getting a nasty disease, you are at risk from, by simply having something sprayed up your nose, wouldn’t you want to? 

From antibiotics to bacon sandwiches

We are at war with an invisible enemy; the foe is bacteria. This war began in 1928 with the accidental discovery of penicillin by Alexander Fleming, though it didn’t fully kick into action until the work of Chain and Florey to purify and mass produce the chemical by 1945 (ironically a significant year another war). We now have a huge array of antibiotics to fight the bacterial enemy and yet the bacteria are still winning the war through their ability to develop resistance and continue to cause infections that are becoming harder to treat. In this blog post I want to look at a well-known resistant bacteria and how resistance emerges. I also want to look at the livestock industry, not just human use of antibiotics, as this has a major part to play in our war with resistance.

I’m sure many readers will have heard of MRSA (short for methicillin resistant Staphylococcus aureus), though not necessarily all will know what it is. S. aureus is a gram positive bacterium, meaning it takes up the gram stain used to classify bacteria. It is just one of the 500-1000 bacterial species that call us humans home and often makes up part of our skin flora (the bacteria is commonly found living on the skin of healthy people). As a slight aside, it is interesting to note that humans are in fact more bacterial than they are human with roughly ten times as many bacterial cells as human cells on, and in, the average human being, S. aureus is just one of the many bacteria that can make up part of this so called microbiome. That takes care of the SA part of MRSA, so onto the MR part. Methicillin is a drug in the penicillin class of antibiotics. This class of antibiotics are known as beta-lactams, and are/were effective against gram positive bacteria (I say ‘were’ due to the prevalence of resistance). When gram positive bacteria are produced they need to form a cell wall made of many peptidoglycan molecules cross-linked with each other (peptidoglycans are amino acids, the building blocks of proteins, linked to sugar molecules). The formation of this wall protects the bacteria from its environment so it can survive. The penicillin class of antibiotics blocks construction of the wall which causes a bacterium to swell, as water enters, and eventually burst. When first described, MRSA were a group of bacteria capable of blocking the action of methicillin, so to allow the production of a stable cell wall in the presence of the drug. MRSA are now resistant to most penicillin based antibiotics, yet the name has stuck.

MRSA is not the only bacteria which have become resistant to antibiotics, but it is constantly hitting the headlines due to its prevalence in hospitals, hence why I have used it as an example here. The question to ask now is why we have resistant bacteria in the first place; the answer lies with natural selection and evolution. Natural selection can be broadly defined as the selection of advantageous traits that promote survival of an organism. Normally I would give an example of this and then move back to my main point of bacterial antibiotic resistance; however, in my view, bacterial resistance is one of the best examples of natural selection at work. As I mentioned earlier, S. aureus is often found on the skin of healthy people without causing any issues. However, if it gets under the skin or into other areas of the body it can cause an infection (impetigo, for instance). If this happens a doctor would prescribe an antibiotic to the patient which, over time, would kill the bacteria and cure the infection. The aim of the bacteria is to survive and grow, so the presence of a killer drug is bad news. The antibiotic is a ‘selection pressure’ that forces the bacteria to evolve in order to survive. If even a single bacterium develops resistance to the antibiotic (an advantageous trait), through a mutation, it will be at a huge advantage since all the fellow, non-resistant, bacteria that are clogging up space and using up resources will be wiped out by the drug. This leaves the lone mutant bacterium with all the space and resources it needs to thrive. This resistant bacterium will rapidly multiple and form a whole new colony of bacteria that are completely unaffected by the drug; giving a resistant strain.

The use of antibiotics can lead to the development of resistant strains of bacteria; however, it is an inescapable fact that we need to treat patients who have bacterial infections. What is avoidable is the unnecessary overuse of antibiotics seen around the globe. Before the issue of antibiotic resistance came to the fore-front of medical thinking it was common for antibiotics to be used for the wrong thing, such as a cold. Most common colds are caused by rhinovirus which, needless for me to say, is a viral infection. Antibiotics are completely useless against viruses since the drugs interfere with bacterial replication; a virus replicates inside a host cell, hidden away from any effects of an antibiotic. Cases of antibiotics being used to treat common colds and other viral infections has, for the most part, stopped since it was realised that this stupid overuse was leading to resistance.

The overuse of antibiotics in humans has, to an extent, been brought under control since we now understand the risk it poses. However, the story does not stop here. At the end of the Second World War, as the antibiotic era was blooming, people began to notice that feeding antibiotics to livestock made them grow faster (we still aren’t sure why exactly). This was a fantastic finding due to the obvious shortage in quality animal feed at the time and the need for a kick-start to the agriculture and livestock industries following the war. Unfortunately, just as with humans, the use of antibiotics for farm animals promotes the emergence of resistant bacteria. These bacteria can easily cause infection within the livestock which comes with obvious economic issues, but somewhat more worryingly these bacteria could easily get into the human population and cause disease that we would struggle to treat. This fact was noticed fairly early on when the EU banned the use of antibiotics used to treat humans for use in livestock in the 70s. Even with this ban, and numerous others around the use of antibiotics to promote growth, the amount of antibiotics consumed by livestock is still double that used by humans; creating a dangerous environment for the emergence of resistant bacteria.

The overuse of antibiotics is something that needs to stop; otherwise MRSA is likely to become the least of our worries. To that end it seems the world needs to follow Denmark’s lead. Denmark is the world’s largest exporter of pork, with 90% of its produce being shipped off elsewhere. At the turn of the century the Danish pork industry decided to follow the lead of its poultry industry two years previously and agreed to stop using antibiotics for growth. Since then, the use of antibiotics has dropped by around 60%. Many argued that stopping the use of antibiotics would lead to a collapse of the industry, but since 1994 the pork production of Denmark has actually risen by 50%. So not only are they giving the world more bacon sandwiches, they are also reducing the risk of giving the world highly resistant bacteria.

We are in danger of losing our war against bacteria since resistance is emerging faster than we can discover new antibiotics. If we continue to unnecessarily overuse antibiotics and drive the evolution of resistant bacteria we are shooting ourselves in the foot. The obvious place to start the reduction of antibiotic use is in the livestock industry since, as Denmark has shown, it is not essential to have antibiotics for the industry to survive. The first step would be to stop vets making a profit from the sale of antibiotics to farmers (a blatant conflict of interest), followed by the implementation of a good surveillance system to monitor the use of the drugs. If we can curb our use of antibiotics it is likely to extend their shelf life, which will in turn buy us more time to find new and improved antibiotics or to work towards alternatives. If we continue down the path of promoting the emergence of antibiotic resistant bacteria we are in danger of heading back to a pre-antibiotic era in which what is currently a simple and treatable infection could become life threatening.