The first antibiotic
The discovery of penicillin by Alexander Fleming in 1928 revolutionised the treatment of bacterial infections. Ironically Fleming discovered it by accident when some culture plates he was growing bacteria on became contaminated by a mould. The mould (which turned out to be penicillin) was killing off the bacteria, a chance finding that would lead Fleming and other researchers to make arguably the biggest medical breakthrough of the 20th century.
Initially hampered by a lack of funds, Fleming could not get much further with his research. World War 2 brought about a major change. After entering the war in 1941, the US government gave $80,000,000 to fund the development of penicillin. By 1943 it was being mass produced and the 1940s and 1950s saw the development of other antibiotics. (1)
Awareness of drug resistance was a concern from the outset
Fleming warned from the start that overuse of antibiotics would render them less effective. In his Nobel Lecture of 1945 he said: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant." (2)
From the outset the possible limitations of antibiotics was recognised, namely that bacteria would become immune to them, a phenomena known as antimicrobial resistance (AMR.) AMR has the potential to be as significant a threat to humanity as any pandemic the world has seen to date, including COVID-19.
A recently published study in the Lancet looked at 204 countries and analysed all the available data on causes of death from 23 known bacterial pathogens (a pathogen is a bacteria, virus, fungi or parasite known to cause disease.) (3)
Researchers looked at 471 million individual case notes and their findings are stark. An estimated 3,500 people are dying worldwide every day because of AMR and in 2019 alone at least 1.2 million deaths were directly attributable to it. In other words, 1.2 million people died from infectious diseases that previously were treatable.
By contrast 860,000 people died from HIV & AIDS and 640,000 died from malaria in 2019 - high numbers but still much lower than the AMR death number.
The highest AMR death rates were seen in sub-Saharan African countries and young children are the most vulnerable. One in five deaths caused by AMR were in children under the age of five. (4) (5)
How does resistance develop?
It is important to understand that in AMR it is the pathogen that becomes resistant to antibiotics not our bodies. Bacteria, viruses, fungi and parasites can all develop resistance to the drugs supposed to kill them.
They do this by making specific proteins that protect them from the drug treatment. They then alter their DNA structure so that all future strains have the genetic code needed to continue making those proteins and remain resistant. Resistant pathogens from one particular strain of pathogen can also pass on these genetic resistance codes to other pathogens from different strains compounding the problem.
Resistance to drugs can take many forms.
Some pathogens develop a thicker outer membrane on their cells which stops antibiotics from entering them. Others have found ways to pump the drug out through their cell walls before it has chance to kill them whilst some are able to destroy the drug completely by using enzymes to break it down.
Many pathogens use all of the above mechanisms simultaneously making them even more able to resist drugs which has given rise to their nickname as "Superbugs."
Alongside this, antibiotics (which work only against bacteria) can also kill off our so-called good bacteria which often help in the fight against infections. This unwanted side effect gives the drug resistant bacteria an even greater advantage. (6)
What will the future bring?
In November 2021 the WHO (World Health Organisation) declared AMR one of the top 10 global public health threats facing humanity driven primarily by the misuse and overuse of antimicrobial drugs. The human and financial cost of this can not be overestimated.
People will require longer hospital admissions for resistant infections as they need to be given second and third line drugs which are also more expensive. There will be more deaths from previously curable infections and people undergoing particular treatments that increase the infection risk, eg: chemotherapy treatment for cancer or major operations, will be at an increased risk of developing infections that can no longer be treated. Medicine could effectively go backwards and people will die from infections we could once easily treat.
The WHO drew particular attention to the emergence of bacteria that are resistant to every drug we currently have.
There is not a new array of antimicrobial drugs in the pipeline either. The technology behind their development is not advancing at the same rate seen in other drug fields. For example vaccine research and development is moving fast, in part because of COVID-19, as is cancer drug research.
However, the WHO is warning us that, unless we change the way we are using antimicrobial drugs now, any future ones will simply fall prey to the same problems. (7)
It is not just the use of these drugs in humans that has caused the problem, their overuse in animals (especially farm livestock) and in food production has played a major role too.
At the same time poor infection and disease control measures and factors such as a lack of sanitation and hygiene allows resistant organisms to pass between humans, between animals and humans or move from contaminated food into humans and animals. This affords them more and more opportunities to develop further layers of resistance.
What can we do about AMR?
COVID-19 has made us all familiar with the concepts of hand washing, face masks and general good hygiene measures as a way to decrease the risk of catching it. Measures such as these can help reduce the risk of picking up many other infectious illnesses. Whilst I am not advocating living under COVID-19 restrictions for evermore, some measures such as easy access to hand sanitiser in public places such as shops and train stations could go some way to helping prevent infections in the first place. If some infections can be prevented in this manner then the need for treatment of them will never arise.
However AMR is a complicated problem without one single solution. The use - and misuse - of antimicrobial medications across the human, animal, food and plant worlds all needs to be tackled.
The WHO implements a "One Health" approach to public health which it defines as: "...an approach to designing and implementing programmes, policies, legislation and research in which multiple sectors communicate and work together to achieve better public health outcomes." (8)
One Health focuses on three key areas: food and water safety, the control of diseases that spread between animals and humans and combating drug resistance.
It recognises that a multi-factorial approach is needed in which different sectors work together for the common good.
Alongside this, far greater investment is needed in the research and development of new antimicrobial medicines. In 2017 the WHO developed the Priority Pathogens list, a list of the pathogens it was most time critical to find new antimicrobial drugs for. The list will be updated this year (2022) but there are still large gaps in the research of pathogens we most need new treatments for, primarily because of a lack of investment.(9)
A high profile report commissioned by the UK government in 2014 - The Review on Antimicrobial Resistance - predicted that by the year 2050 AMR could be killing up to 10 million people per year. (10)
(COVID-19 has caused just under 6 million deaths worldwide at the time of writing over the past two years.) (11)
Some scientists have refuted the figures found in the report citing the fact there are too many uncertainties around infectious diseases to allow for such modelling. They called for studies to be carried out across multiple countries across the world. The Lancet study did exactly that and it is currently the most comprehensive set of data available on the burden of AMR. (12)
The Lancet report authors stressed the need to start measures to control AMR now by using existing antibiotics wisely, monitoring and controlling infections better and funding research into new drugs.
Tim Jinks is the head of the drug-resistant infections programme at Wellcome Trust and he summarised the situation perfectly when he said: "The COVID-19 pandemic has highlighted the importance of global collaboration: political leaders, the healthcare community, the private sector and the public working together to tackle a global health threat. Like COVID-19, we know what needs to be done to address AMR, but we must now come together with a sense of urgency and global solidarity if we are to be successful." (13)
We need to heed his warning.
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