Many of us can safely say that without antibiotic treatment, we or a loved one would not be alive today. Yet because of their effectiveness, low cost and relatively wide availability, these miracle drugs are often taken for granted. Since their discovery only 75 years ago, antibiotics have been losing their effectiveness at an alarming rate, leaving even the most trivial infections untreatable. Despite this, research into their development is waning, and it has been over 30 years since the last new antibiotic class, linezolid, was discovered. Furthermore, the bugs causing these infections are rapidly evolving to become tougher, gaining genes for antibiotic resistance and modifying themselves to prevent the antibiotics from working. However, this lack of antibiotic development has little to do with the scientific research itself. Instead, the main hurdles include a lack of financial incentives for drug companies to invest in antibiotic drug discovery research and a lack of government policy to make this research attractive to the private industry.
In 2011, the World Health Organisation cautioned that the currently available antibiotics were quickly becoming ineffective and action was needed to avoid a public health disaster; yet no formal plan of attack was created. Thankfully, this issue is re-emerging and regaining public attention. In her annual report published last month, Professor Dame Sally Davies, England’s Chief Medical Officer (CMO), flagged antibiotic resistance as a national health crisis, stating that it should be placed on the national risk register, alongside such threats as climate change and terrorism. She argues that if the catastrophic threat of antibiotic resistance is not immediately tackled, Britain’s health system will regress 200 years. If antibiotics become completely ineffective, any standard medical procedures that leave patients susceptible to bacterial infections, such as organ transplants or anti-cancer chemotherapy, will be rendered impossible due to the extreme risk of infection.
The antibiotic-development pipeline has dried up due to the complex nature of research involved in drug development and the plateauing of antibiotic discovery from everyday natural sources, such as the common mould that gave us penicillin. Researchers have picked all the low hanging fruit, making it much more difficult and costly to develop new antibiotics.
Most importantly, antibiotics are not particularly profitable. Only a short course is required, compared to more lucrative drugs, such as cholesterol-lowering medication, which a patient will take every day for potentially the rest of their life. Also, despite a growing population and increasing antibiotic use, the value of the worldwide antimicrobial market is shrinking, from $16.1bn in 2005 to $14.4bn in 2010. This has been attributed to a number of factors, such as decreasing manufacturing costs. Furthermore, because new antibiotics are primarily reserved for bacteria that are resistant to other “first-line” drugs, they will only be used in a very select population, and so will not be very profitable. Physicians reserve new antibiotics for serious cases to minimise the development of resistance to these new variants and to keep these options as effective as possible; if their use is restricted to hospitals, exact dosage amounts and times can be controlled.
Because of the high cost, high risk and low reward of developing new antibiotics, drug companies do not view antibiotic research and development (R & D) as a profitable endeavour. Today, only two of the largest pharmaceutical companies, GlaxoSmithKline and AstraZeneca, still have active antibiotic R & D programs, in contrast to 1990 when there were almost twenty.
Although it is tempting to hold drug companies accountable, there has been a recent shift to look toward government bodies to take responsibility for this lack of research. Ideally, governments and public health organisations should be actively investing in the development of new drugs or subsidising research to make it more attractive for private companies.
To promote this message, community groups have formed to encourage governments to act and evoke change at the policy level. One of the most active campaigns in the UK, Antibiotic Action, is associated with the British Society for Antimicrobial Chemotherapy (BSAC), and lobbies the government to provide funding for antibiotic development. This burgeoning campaign, headed by Prof. Laura Piddock, aims to “educate all on the need for new antibiotics, by collaborating with likewise initiatives globally.” This is achieved by working with the Department of Health to deliver the recommendations of the CMO’s report and disseminate a strategy on fighting antimicrobial resistance to the government. A newly established political group, the All Party Parliamentary Group on Antibiotics, chaired by the UK Shadow Minister for Health, Jamie Reed, will add additional force to this cause.
So why hasn’t the public noticed this microscopic war and why does this important issue continue to be ignored? Firstly, while many of us are aware that bacteria can become resistant to antibiotics, few understand how bacteria develop this resistance or how pressing the problem is. This is understandable, as from our everyday experiences antibiotics seem to work most of the time, and if there are complications with treatment and we do not get better, different antibiotics are simply prescribed. However, scientists are warning that these back-up options are running dangerously low, as bacteria evolve to become more resistant. There are now many examples of “untreatable superbugs”, that is, bacteria resistant to all available antibiotics.
Bacteria develop resistance quickly and in surprisingly clever ways, such as by pumping the antibiotic out of the cell or modifying their body parts so that the antibiotic is no longer effective. Bacteria have managed to survive for roughly 3.5 billion years, whereas we humans have only been around for a measly 22 million years. We have entered into an escalating arms race that, unfortunately, was lost before it was even begun. Bacteria with armour against the naturally derived antibiotics we use today have always existed, and with millions of years of exposure to these natural sources, resistance mechanisms have developed to them over time. For example, ancient bugs resistant to modern antibiotics have been found in Siberian permafrost, over 30,000 years old, as well as preserved in a four million year old cave in New Mexico. Current human use (or over-use) of antibiotics has simply encouraged the growth and spread of these resistant bacteria.
Another misconception is that only human-associated, pathogenic bacteria can become resistant to antibiotics. However, these are just the best-publicised cases. For instance, hospital outbreaks of the notorious “superbug”, methicillin-resistant Staphylococcus aureus (MRSA), are causing deaths in the UK and around the world on a regular basis. In reality, antibiotic resistant bacteria are everywhere: on exotic sharks, wild Arctic birds, food producing animals, in the soil, and even in water. This increasingly widespread resistance is due to an antibiotic usage “web” where antibiotics are pumped into the environment – whether on food-crops, in food-producing animal feed, or the run off from our sewage – and can end up in our water sources. More than half of the antibiotics produced go toward animal use, a statistic that scientists have fought to reduce. For instance, in 2006, antibiotics were banned from being put in animal feed as growth promoters in EU countries, but in countries that rely heavily on agriculture for income, such as Australia and the USA, this remains common practice.
Antibiotic resistance is a worldwide problem. Some of the newest and most potent antibiotic resistance genes originate in developing countries, mainly due to lax antibiotic restrictions where in some cases no prescriptions are needed, leading to self-diagnosis and misuse. A prime example is the newest “superbug” outbreak, emerging in 2009 in a rod-like bacterium called Klebsiella that carried a new resistance gene, New Delhi Beta-lactamase (NDM-1), and was spread from India globally via returning travellers. The NDM-1 gene renders the infection resistant to virtually all antibiotics, meaning these infections have high mortality rates and are exceptionally dangerous compared with standard local infections.
Resistance genes themselves can spread throughout bacterial populations, and even jump between unrelated bacterial species. This is equivalent to a poisonous spider transferring its venom genes to another animal, either to a predator, such as a lion, creating an incredibly dangerous animal, or (perhaps even more terrifying) to a tame animal, like a domestic dog, which lives among us and may occasionally bite us but was previously essentially harmless. The latter example reflects the common case of antibiotic resistance genes in our “good” bacteria that mostly live in our gut and help us digest food, but occasionally make us sick. For instance, helpful gut bacteria E. coli can cause infection if they accidentally move into the urethra, resulting in a urinary tract infection. Good hygiene can prevent this transfer of bacteria around the body and reduce the chance of these infections.
Apart from minimising the use of current antibiotics and investing in the development of new ones, there is little we can do to stop the spread of these microscopic monsters. However, one possible approach is to search for pre-existing antimicrobials in untapped and perhaps unconventional sources. For instance, researchers in China recently found a potent antimicrobial compound in the blood of giant pandas.
There are also some promising alternatives to antibiotics. One example is phage therapy, where tiny viruses that eat bacteria, called phages, are pumped into the bloodstream and destroy the bacteria by dividing inside them and bursting their cells. Russian scientists have been developing this method for over 50 years, but it has been relatively unused in western medicine. This is mainly due to the dangerous potential for severe side effects from phage therapy, where our immune systems over-react against the phages, causing harm to our own cells. Another promising area of research has been in “natural therapies” such as manuka (or medical) honey to treat bacterial infections. Although this is effective as topical (on skin) treatment, one issue is that the active compound is so complex it has not yet been extracted or purified. This means a tablet for ingestion cannot be made, making dosing and treatment of serious infections difficult.
There is hope for tackling bacterial resistance through the development of new technologies to discover novel strains of antibiotics. For example, the exponential improvements and decreasing cost of DNA sequencing technology has meant that routine sequencing of bacterial genes has become recently accessible to scientists in the last few years. It is an invaluable tool to researchers, such as myself, who systematically trawl through genes of bacteria to find points of weakness that can be used to kill the bacterial cells, without harming our own, and may developed into a new drug target. Hopefully, these new drugs will be able to provide a solution for the increasing need for antimicrobials in modern medicine, or at least delay resistance for another 50 years.