We need some CRE-ative solutions

“Superbug” is an expression we hear far too often. Due to our excessive use of antibiotics over the past 65 or so years we have excelled this term from a potentially comical image of a flying inset that fights crime, to something we genuinely need to fear in a medical context. Admittedly, I am not a fan of the term “superbug,” but it is certainly catchier than the more accurate description of drug resistant or multi-drug resistant bacteria. The bacteria that will most likely spring to mind as being “superbugs” are MRSA and C. difficile. Both of these bacteria are well known to plague hospitals worldwide and cause potentially life-threatening disease in those people at their most vulnerable (in hospital for some other aliment). While MRSA and C. diff. are well established as health care-associated resistant bacteria, a new player is starting to come to the attention of healthcare officials and its emergence is being greeted with genuine fear.

Before discussing these new resistant bacteria I’d first like to talk about why we have resistant bacteria at all. In one sense, we can blame evolution. Bacteria are always looking to survive and will evolve to deal with anything that threatens this. The emergence of resistance is a wonderful example of the process of natural selection that drives Darwinian evolution. Let us consider a situation in which a patient has a bacterial infection. If this patient takes antibiotics these will kill the bacteria and aid the patient’s recovery. However, not all bacteria are created equally and when they multiply the progeny can carry mutations that set them slightly apart from their parent. It is possible that these mutations confer the bacteria with a slightly increased chance of survival against the antibiotics. If this occurs then this, potentially lone, bacteria will survive at the expense of all the others and will continue to grow (‘survival of the fittest’). All the competition for space and recourses has been removed due to the death of all other bacteria so this resistant bacterium will thrive. In the face of continued antibiotic treatment any new mutations that confers even greater protection will cause the same affect, continually selecting the bacterium that has the best protection from the affects of the antibiotic. The logical end point for all of this is that a bacterium will emerge that is completely protected from an antibiotic and it will thrive and spread.

MRSA - probably the best known "superbug"

While it is easy to blame evolution for the emergence of resistant bacteria, that is not the full story; we as humans need to take a fair share of the blame. Since the discovery of a process for the mass production of penicillin shortly after the Second World War, we have overused antibiotics. Antibiotics have been overused in the context of bacterial infections and most likely have been used to treat bacteria that are not susceptible to that drug (only certain antibiotics are effective against certain bacteria). However, more worryingly there are many cases of antibiotics being used to treat infections not caused by bacteria, such as the common cold, which is ridiculous since the drugs only work on bacteria (like using a cough sweet to treat a heart problem). The reason that overuse, and incorrect use, causes an issue is that we have billions of bacteria inside us; put these in an antibiotic context and you promote the emergence of resistance. Consider the fact that MRSA is a strain of the bacteria Staphylococcus aureus, a bacterial species that the vast majority of us have naturally in our lungs and on our skin, the only difference is MRSA has evolved resistance to the antibiotic methicillin.

MRSA and other resistant strains of bacteria are dangerous, however we do still have some “last line of defence” antibiotics that can be pulled out at the last minute to save the day like a cheesy action film. However, more and more cases of a new type of resistance are being seen, particularly in the USA, known as CRE. CRE stands for carbapenem resistant Enterobacteriaceae, with carbapenem being one of our few remaining “last line” antibiotics. Enterobacteriaceae are a bacterial family that include many well-known bacteria such as E. coli, Salmonella, Shigella and Y. pestis (which caused the Plague).  These are the well-known species in the Enterobacteriaceae family; however so far, most cases of CRE have been seen in Klebsiella and Enterobacter species that cause lung, intestinal and urinary tract diseases.

CRE bacteria have been spreading through the USA since their first detection about 5 years ago. Studies have suggested that these bacteria are endemic in major population centres such as New York, LA and Chicago (a report suggests that 3% of patients in intensive care units in Chicago carry CRE bacteria). There are also small pockets of CRE throughout other areas of the USA. So far CRE cases have been confined to health care facilities such as hospitals and care homes, as is the case with other “superbugs” such as MRSA. However, as with anything there is always the potential for spread outside of these facilities. The thought of spread is a worrying one when you consider the fact that CRE infections currently carry a reported 40% mortality rate, much higher than that of MRSA. If I was writing this blog for a newspaper this is where I would leave that statistic, 40% of people who get CRE die, everyone be scared and fearful! However, mortality rates are a pretty useless statistic as they rely on the ability to detect every single case of CRE to be accurate, yet chances are, only the most serious (and therefore life-threatening) cases are likely to be detected, skewing the data in favour of a higher death rate. When you also consider that until recently CRE has not garnered much attention, meaning no-one has really been looking for it, you get a further skewing of the data (only the most serious will be taken notice of). There is also difficulty in detecting CRE bacteria since carbapenems are not readily used, in the hope of preventing the emergence of resistance. This is not to say we shouldn’t consider these bacteria as inconsequential and we should (as we are) be treating them with a well-deserved level of respect.

The bottom line is that CRE bacteria are resistant to our last remaining antibiotic against this family of bacteria. All that we can do at this stage is prevent, the age-old techniques of rigorous hand washing, protective clothing and isolation are the main ways to protect from CRE infection. If someone becomes infected there is no effective treatment, with the exception of some old antibiotics that have been shelved for years due to their high toxicity (not necessarily something you’d want to take).

CRE bacteria are something we should be rightly fearful of, however they also bring to the forefront a gapping hole in our medical research. While we have some new and improved antibiotics in the pipeline, very few of these are though to be of any use against CRE, and there is very little incentive for the major drug companies to look for ways to tackle CRE. The problem lies in the fact that antibiotics just don’t make enough money. Why would a major drug company want to spend a fortunate making a drug that is used for maybe a couple of weeks, until the patient recovers, when they could spend their money making drugs to target chronic diseases that will need to be taken for the rest of a patients life. Not only is the treatment time short, but also resistance emerges so quickly that any drug produced could rapidly become obsolete, making the money spent useless. It sounds wrong to neglect people who could die from an infection on the basis of economics, but unfortunately, that is how it is, in the bluntest (and a slightly cynical) way.

I titled this blog post as the fact that we need some creative solutions, both for the play on the CRE bacteria naming and because, simply put, we do. There are ideas out there, such as the use of phage to kill bacteria. Phage are viruses that only infect bacteria so if we can find a way to use these then it may provided a good alternative to antibiotics. There is also work being conducted to look for new and untapped sources of antibiotics with the discovery of new fungi and bacteria (which produce antibiotics) in obscure locations such as caves and oceans, however, as I’ve alluded to, there is a shortage of funding in these area.

Process of conjugation, one of the main ways resistance spreads

One potentially promising area of research may lie in targeting the mechanism used by bacteria to spread resistance. Resistance is controlled by the production of protective proteins from genes. It is very common that these genes are located on mobile genetic element known as a plasmid (stick with it as I will clarify what that means). Like us, bacteria have a genome that contains all the instructions needed to produce a functional bacterial cell. However, in addition to the genome many bacteria can have addition chunks of DNA (plasmids). These extra units of DNA float around the cell, separate from the rest of the genome, and can be passed from one bacterium to another. Think of this like books, if the genome is a full instruction book for producing the bacteria then a plasmid, is like a page taken from another book. These plasmids (extra pages) can move between bacteria through a structure known as a pilus, in a process often termed bacterial sex (due to some obvious similarities – Google it). If we can find ways to block this process, correctly known as conjugation, then we may be able to stop the spread of genes that confer resistance and maintain the efficacy of our current stock of antibiotics. However, as it stands, this is just a hypothesis.

CRE bacteria are worrisome, they are resistant to pretty much all of our current stock of antibiotics and the number of cases are on the up. There is a reported death rate of around 40% for CRE infection, and while this may be slightly skewed, it is still clearly a dangerous situation we find ourselves in. We need new and innovative ways to tackle these bacteria as simply stopping the spread with preventative measures can only go so far. However, whether the funding will reach the research into these areas is yet to be seen.