Death by tonsillitis: imagining a world without antibiotics

Amy Cain
May 18, 2013

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.


All by
Amy Cain