Antibiotic Resistance – Global
Antibiotic resistance is one of the main threats to global health, food security, and development today. While antibiotic resistance is a naturally occurring phenomenon, it has been dangerously accelerated due to the misuse of antibiotics in humans and animals. As the number of antibiotic-resistant bacteria is growing, it is threatening our ability to treat common infectious diseases such as pneumonia or urinary tract infections and hindering our ability to keep using antibiotics to aid other life-saving treatments, such as chemotherapy and radiotherapy.
Antibiotic resistance has first been noted by Alexander Fleming, alongside his ground-breaking discovery of the first antibiotic, penicillin. When accepting his Nobel Peace Prize for penicillin, at the time hailed as the “miracle drug’’, he warned of the dangers of unchecked and chaotic use of antibiotics, stating that this will eventually render the drugs useless and once again leave us defenceless in front of infections.
Without urgent national and international action, we are heading towards a post-antibiotic era, in which common infections and minor injuries can kill once again. The WHO has estimated that by 2050, antibiotic resistance will become the biggest killer in the world, killing an estimated 10 million per year, more than even cancer. Antibiotic resistance is already currently taking an estimated 700,000 lives each year.
The rise of antibiotic resistance is not only a national problem but a global problem as well, mainly due to the nature of antibiotic-resistant bacteria. Bacteria are constantly evolving and changing, they can not only adapt resistant mechanisms on their own, but they can even transfer their genetic material encompassing resistant mechanisms onto other bacteria or in the environment around it. The transfer of bacteria can occur from human to human, human to animal, or vice versa or through the environment. Due to its versatility, bacteria are often impossible to contain and measures usually used in viral outbreaks, such as the recent COVID-19 lockdowns, would not be able to effectively target it.
Bacteria resistance to a huge number of antibiotics has already occurred, with the most notable ones being carbapenem-resistant Enterobacteriaceae, MRSA, Vancomycin-resistant Enterococci, and Mycobacterium tuberculosis. The Carbapenem-resistant Enterobacteriaceae are resistant to the carbapenem class of antibiotics, considered the last resort antibiotic in Enterobacteriaceae infections. This means that bacteria such as Escherichia coli and Klebsiella pneumonia are no longer treatable, leaving patients to die from previously treatable diseases such as pneumonia. In the same way, Mycobacterium tuberculosis can lead to tuberculosis becoming incurable. Long-term exposure to MRSA, the Methicillin-resistant Staphylococcus aureus, can lead to skin infections, urinary tract infections, and even sepsis. This specific bacteria is often found in hospitals, with MRSA bacteria gained from hospitals being more likely to lead to complications.
The brunt of antibiotic resistance will be disproportionately focused on low and middle-income countries, mainly due to the poor health care systems present. Due to the highly spreadable nature of bacteria, poor health care systems won’t be able to keep up and prevent or contain antibiotic-resistant bacteria. In these countries, antibiotics are often handed out without prescriptions and their use is not monitored in hospitals or pharmacies. This not only increases the prevalence of antibiotic-resistant bacteria but also creates more chances for the bacteria to communicate and evolve resistant mechanisms. Additionally, the high use of antibiotics in animal agriculture in these countries has already lead to the creation and spread of several antibiotic-resistant bacteria. A prime example would be the appearance of colistin-resistant bacteria in 2016 on a farm in China, where colistin was often used in animal agriculture. Colistin is considered the last resort antibiotic for all infections and is very seldom prescribed in practice unless absolutely necessary due to the side effects associated with the strong drug. China has since banned the use of colistin in animal agriculture. However, colistin-resistant bacteria has already spread to all continents and some low-income countries still use it for livestock.
There have been various responses to this crisis, the WHO and EU have each developed an AMR action plan, with all EU nations developing their own national AMR action plan as well. Both the WHO and the EU have stated that the EU will act as a role model for combating antibiotic resistance. However, the implementation of these plans has encountered several difficulties. From lack of funding, lack of skilled personnel, and lack of proper information centres, these difficulties make it impossible for countries to effectively tackle AMR. With the lack of funding available for the creation of antibiotics, there are very few in the making today. It takes around 1 billion dollars to create antibiotics and around 10 years of research. However, pharmaceutical companies have decided to no longer create antibiotics, as they would not bring back profit. Due to the constantly evolving nature of antibiotic-resistant bacteria, a new antibiotic would only be good for a few years under the current circumstances in the healthcare and animal agriculture sectors, before a bacteria resistant to it is discovered.
"The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism."
Key Facts
700,000
People killed per year (aprox.)
10,000,000
Estimated deaths by 2050
Ongoing since
1928
Major Outbreaks
- Carbapenem-resistant Acinetobacter
These bacteria are now multi-drug resistant and if untreated they can cause blood, lungs, urinary tract infections, and open wounds.
They are often found in the environment, in soil or in water and tend to spread fast in intensive care units.
The WHO declared this outbreak as an immediate emergency, mainly due to the significantly high death rate of approx. 50%.
Where: Global (areas of concern: USA, Europe, Asia, Australia, Israel & South Africa)
- Methicillin-resistant Staphylococcus aureus (MRSA)
These bacteria are multi-drug resistant and are responsible for several severe infections that are now very difficult to treat. If untreated, MRSA usually manifests as a red bump on the skin accompanied by a fever, both symptoms getting worse over time and becoming life-threatening.
As MRSA originated from a hospital setting, it is very commonplace in hospitals, nursing homes, and other healthcare settings. While it affects everyone, it is particularly devastating to those with weak immune systems or those who have recently undergone surgery.
Where: Global
- Candida Auris
This fungus is resistant to multiple antifungal medications and if untreated can lead to severe candida infections which in time turn life-threatening.
Another area of concern regarding this outbreak is the difficulty with which it can be identified, making it very easy to miss in hospital settings. Many outbreaks have occurred in intensive care units due to this. The WHO has stated that it might even be responsible for around 600,000 infections each year worldwide.
Where: Global (areas of concern: USA, Spain, India, Venezuela, Pakistan)
- Clostridioides difficile
These bacteria are multi-drug resistant and most commonly affect people who have recently been treated with antibiotics. If untreated this can lead to severe diarrhea and colitis and can be life-threatening in the long run.
Where: Global
- Carbapenem-resistant Enterobacterales
These bacteria are often referred to as nightmare bacteria, due to their high mortality rate, their vast resistant mechanisms, and high spreadability. They are often immune to most existing antibiotics with some of them proving to even be immune to all existing antibiotics. If untreated, they can leave people with untreatable infections which will eventually lead to death.
Depending on the strain, Enterobacterales can have various effects, from pneumonia due to the Klebsiella pneumoniae bacteria to severe diarrhea and colon damage from Escherichia coli.
Where: Global
- Drug-resistant Neisseria gonorrhoeae
These bacteria are multi-drug resistant and a large portion of them have now even developed resistance to the standard combination antibiotic therapy opted for by most healthcare systems worldwide. If untreated, these bacteria can cause gonorrhea, a sexually transmitted disease that causes pain during urination, discharge and can lead to life-threatening complications such as pelvic inflammatory disease or septic arthritis.
Where: Global (areas of concern: Denmark, France, Japan & United Kingdom)
- Drug-resistant Campylobacter
These bacteria are now multi-drug resistant and infections with resistant strains usually take longer to treat and lead to a higher risk of severe complications. If untreated, these bacteria can lead to severe diarrhea which in time can lead to life-threatening complications.
These bacteria are usually transmitted through contaminated water or food and can be found in undercooked or raw meat.
The CDC has declared that in 2017, around 25% of all Campylobacter bacteria was now resistant to its first-line treatment, ciprofloxacin.
Where: Global
- ESBL-producing Enterobacteriaceae
These bacteria have learned to produce a specific enzyme called ESBL which works in breaking down antibiotics, rendering them ineffective. Depending on the strain, Enterobacterales can have various effects, from pneumonia due to the Klebsiella pneumoniae bacteria to severe diarrhea and colon damage from Escherichia coli.
Where: Global (areas of concern: Germany, Africa, USA)
- Vancomycin-resistant Enterococci (VRE)
These bacteria have developed resistance to their first-line treatment, vancomycin, and they are commonly spread through poor hygiene. If untreated, these bacteria can cause an array of symptoms, from blood and urinary tract infections to infections of surgical or open wounds. The CDC has reported approx. 5,000 deaths in 2019 due to this resistant strain.
Where: Global
- Multidrug-resistant Pseudomonas aeruginosa
These bacteria are now multi-drug resistant and if untreated can lead to blood and lung infections, as well as infections in areas of the body that have recently undergone surgery. It specifically targets people within intensive care units that are on breathing machines, use catheters, have suffered burns, or have recently undergone surgery.
Where: Global
- Drug-resistant nontyphoidal Salmonella
These bacteria are multi-drug resistant and If untreated can lead to severe diarrhea, high fevers, and focal infections. The most common sources of these bacteria are raw and undercooked meat, eggs, and raw milk or direct contact with infected animals. The overexposure of these animals to antibiotics might be the main contributor to the rise of drug-resistant Salmonella.
Where: Global
- Drug-resistant Streptococcus pneumoniae
These bacteria are multi-drug resistant and if untreated, can lead to bacterial pneumonia and meningitis. There is currently a vaccine for these bacteria that help prevent infections called the PCV vaccine.
Where: Global
- Drug-resistant Tuberculosis
These bacteria are now multi-drug resistant and are responsible for Tuberculosis. This disease manifests through a thick cough, sometimes presenting blood as well, fatigue, fever, and chest pain. While it mainly targets the lungs, it can also spread to other parts of the body including the glands, bones, nervous system, and abdomen.
While TB used to be completely curable, those infected with drug-resistant strains can no longer be treated and face more severe infections.
Where: Global
The Key Actors
One of the main key actors in the AMR crisis would be pharmaceutical companies. Due to the profit-oriented way in which these companies operate, they have decided to stop manufacturing and creating new antibiotics as these have been deemed unprofitable.
As it would take 1 billion dollars and 10-15 years to create a new antibiotic and only 5 years for the bacteria to develop resistance against it and render the antibiotic less profitable, pharmaceutical companies have started to stop the creation of new antibiotics altogether. However, without new antibiotics, we lose an important layer of protection against AMR and a post-antibiotic era only draws nearer. Currently, there is no antibiotic on the market without bacteria with resistance mechanisms against it.
Another way in which pharmaceutical companies affect the AMR crisis is through patents, particularly patents for phage therapy development.
The WHO is the centrepiece in all current global health concerns. In order to combat the current AMR crisis, the WHO has created a global action plan for the next 5-10 years, outlining the key actions that should be taken. Below are the 5 main objectives outlined in this global action plan:
- Improve awareness and understanding of antimicrobial resistance
- Strengthen knowledge through surveillance and research
- Reduce the incidence of infection
- Optimize the use of antimicrobial agents
- Ensure sustainable investment in countering antimicrobial resistance.
Local Governments play a huge role in the AMR crisis. The WHO has asked each country and their governments to adopt their AMR global action plan themselves in order to better fit each country’s specific requirement. Each local government is now responsible for creating its own national AMR action plan and putting systems in place to make sure the plans are being implemented.
Furthermore, the WHO has specifically mentioned that the EU will play as a role model for combating the current AMR crisis and the world is currently looking at the EU for new AMR policies.
The Situation
Classification:
- Endemic
Analyst’s suggestions:
A stronger focus on AMR evidence based-policy making, as there numerous sources of information on AMR spread and very few policies addressing these.
Policies to address and hinder the standardisation of national actions plans to mimic the WHO and EU action plans without addressing each country’s specific AMR needs.
A call for a global coordinated AMR monitoring system.
Action taken by governments and pharmaceutical companies to develop more antibiotics instead of relying on the hopes that an alternative to antibiotics might be discovered.
The creation of a shared pool of AMR data, data collection and technical tools similar to the original C-TAP Covid-19 access pool and the strong stance against IP centred knowledge pools.
More effective funding systems for AMR research and policy making.
AMR awareness programmes and training events for hospital staff on proper AMR containment and monitoring.
Worsening
In November 2021, The Food and Agricultural Organization has declared we may soon be reaching the tipping point for AMR related deaths to start exponentially rising and becoming the number 1 cause of death worldwide.
FAO-OIE-UNEP-WHO joint platform was declared in November 2021 during Antimicrobial Awareness Week in order to deal with AMR in Europe and Central Asia.
Dr Hans Henri P. Kluge, WHO Regional Director for Europe stated that AMR is being pushed towards the back of the agenda, with Covid-19 staying at the fore front of health crises. However, he warns against the persistent lack of urgency relating to AMR.
With the WHO declaring Antimicrobial resistance as one of the top 10 global threats to public health, AMR continues to rise. Resistance rates have even reached an approx 92% for some antibiotics. Antimicrobial resistance is currently responsible for approx. 700,000 deaths worldwide each year and the death rate is expected to rise to a concerning 10,000,000 within the next few decades.
The WHO, EU and national AMR combat plans worldwide have succeeded in lowering AMR infection rates in certain cases, however, they are not enough to keep the public health crisis from growing. These plans have generally failed to tackle hospital transmissions, animal agriculture AMR policies and do not raise enough awareness of the issue throughout the public.
The WHO in partnership with the Drugs for Neglected Diseases Initiative have committed to developing 5 new treatments for the most dangerous resistant bacteria by 2025. However, with the current COVID-19 pandemic taking all the focus from other public health concerns, it seems this might end up being delayed.
As of December 2019, only 42 new antibiotics have gone into clinical development, with only 4 of them hitting the market by today. The most popular AMR combat mechanisms in development, phage therapy, is currently facing a patent and intellectual property crisis Phage therapy scientists have warned that without the opening up of patents and the relaxation of intellectual property rights in the pharmaceutical industry, the further development of the antibiotic replacement therapy will eventually come to a halt and won’t be able to keep up with the AMR crisis.
Timeline of Events
28 September 1928 – Discovery of Penicillin
In 1928, Scottish researcher Alexander Fleming discovered the first antibiotic in his laboratory at St Mary’s Hospital in London and named it penicillin.
The researcher accidentally stumbled upon the discovery when he was researching staphylococcus, a very dangerous bacteria that can cause disastrous infections in patients with weakened immune systems. He left the staphylococcus sample on a plate near a sample of the now named Penicillium notatum mold for 2 weeks and once he returned to his lab he noticed that the mold had developed a mechanism to combat the bacteria.
May 1940 – Penicillin useful in mice
Florey alongside his colleagues, Norman Heatley and Jim Kent, conducted the first experiment showcasing the efficacy of antibiotics. They infected 8 mice with deadly doses of Streptococci and then subsequently administered doses of penicillin to only a few. The ones that didn’t receive penicillin died by the next morning, while the others lived for days and even weeks after infection.
February 1941 – First human use
The first patient to be treated with antibiotics was 43-year old policeman Albert Alexander. The policeman had gotten infected with both Staphylococcus and Streptococcus from a scratch on his face that he got while mending his backyard garden. Fleming and his team attempted to treat the man with penicillin, however, due to the economic and medical restrictions caused by the war, they didn’t manage to extract enough penicillin to cure the patient in time.
While his symptoms had initially improved and the infection subsided, due to the lack of enough penicillin at the time, he eventually relapsed.
February 1942 – First pharmaceutical companies sign penicillin contracts
Following several committee meetings held by the Oxford team, pharmaceutical companies Merck and Squibb agreed to start producing penicillin, with Pfizer following in September as well.
March 14, 1942 – First patient treated
By March 1942, enough penicillin had been produced to treat the first patient, American dancer Ann Miller. The patient at the time was suffering from septicemia and was nearing the end of her life, however, due to her connections she managed to get in contact with one of the British scientists producing penicillin. After receiving treatment, her symptoms rapidly improved and she was cured within the day,
Ann Miller went on to live to 90 years old.
1942 – First Bacteria Resistant To Penicillin.
The first strain of Staphylococcus aureus resistant to Penicillin was recorded in hospitals and by the end of the 1960s around 80% of these bacteria found were immune to Penicillin.
1944 – Penicillin used in WW2
By 1944, penicillin was being extensively used in the treatment of wounded soldiers in the second world war.
1945 – Nobel Peace Prize
Fleming and his colleagues, Florey and Chain win the Nobel Peace Prize in Physiology and Medicine. This sets off the golden age of antibiotics worldwide.
During his acceptance speech, Fleming warns about the consequences of the overuse of antibiotics, antibiotic resistance.
March 1945 – Penicillin available at US pharmacies
Penicillin became available in US pharmacies for the first time.
June 1946 – Penicillin available at UK pharmacies
Penicillin became available in UK pharmacies for the first time.
May 1948 – First antibiotic introduced in livestock feed
After the discovery that adding lower doses of antibiotics to feed on animal farms improved and promoted growth in livestock. The first antibiotic used for animal growth, Sulfaquinoxaline, was introduced as feed-in poultry farms this year.
1950 -1960 – Golden age of antibiotics and signs of antibiotic resistance
This decade is considered the golden age of antibiotic discovery, with most antibiotics used today being discovered during this time.
However, a boom of antibiotics used for non-clinical purposes in animal feed came with the discovery of new antibiotics. In 1951, Germany started licensing antibiotics without a requirement for a veterinary prescription, with Britain, the Netherlands, and the rest of the world following by the end of the decade. While most of Europe tried to regulate to a certain extent, which antibiotics are being used without a license, in the US, only pre-constructed antibiotic cocktails were available for farmers to use as growth promoters. This has led to the US losing control and track over which antibiotic is being used for what purpose.
Additionally, the transfer of antibiotic-resistant mechanisms was noted for the first time in Japan during the mid-1950s. However, the discovery was met with extreme skepticism in the West.
1960 – Concerns rise around antibiotic resistance
In the 1960s, concerns have arisen around the nature and impact of antibiotic resistance, due to the rise of antibiotic-resistant strains to Salmonella. These strains have been linked to calf disease.
1961 – Methicillin-Resistant bacteria and MRSA
The introduction of Methicillin in UK hospitals has led to the first methicillin-resistant S. aureus bacteria strain also known as MRSA. MRSA-caused infections are considered to be very dangerous in hospital settings as they often lead to severe complications in vulnerable people. By the end of the 1960s MRSA had spread all over the world.
1964 – Molecule structure revealed for the first time
The full molecular structure for penicillin has been revealed for the first time by Dorothy Crowfoot Hodgkins. This discovery has lead to Hodgkins receiving the Nobel Prize in Chemistry that year.
1967 – Strains of .S pneumoniae become resistant to Penicillin
First case of Penicillin resistant S. pneumoniae was identified in Australia.
November 1969 – Concerns over antibiotic use in animal feed
The Joint Committee on the Use of Antibiotic in Animal Husbandry and Veterinary Medicine in the UK, has released a report on the potential hazardous consequences of low dose antibiotic administration in animal feed and veterinary centres.
1976 – Spread of Gonococcus resistance
With the introduction of Penicillin as a treatment for Gonorrhea, the first bacteria strains resistant to Penicillin emerged.
1986 – Sweden ban antibiotics in animal feed
In 1986, Sweden banned the use of antibiotics as growth promoters in animal feed.
24-27 October 1997 – WHO raises concerns on antibiotic resistance
During its 1997 October meetings, the World Health Organization has raised concerns over the use of antibiotics in animal feed for growth promotion and illness prevention.
June 1998 – WHO re-examines previous meetings
During its 1998 June meetings, the World Health Organization analysed and warned over the use of fluoroquinolones in animal feed and the impact antibiotic resistance can have on both human and animal life.
June 1998 – EU bans 4 antibiotics in animal feed
Following the WHO meetings, the European Union has decided to ban the use of virginiamycin, spiramycin, tylosin phosphate and zinc bacitracin as animal growth promoters.
April 1999 – Macrolides Tylosin and spiramycin banned in EU animal agriculture
Following the initial ban of 4 antibiotics, in 1999, the use of Macrolides Tylosin and spiramycin in animal feed and growth promotion was banned within the European Union.
January 2001- WHO Global Strategy
In 2001, The World Health Organization released the first Global Strategy to fight the rise of AMR, the WHO Global Strategy for Containment of Antimicrobial Resistance.
18-26 May 2015- World Health Assembly
During the 2015 World Health Assembly, all countries have agreed to adopt and implement the Global AMR actions plans. World Antibiotic Awareness Week was created in 2015 in order to raise awareness of AMR.
2016 – Dual Antibiotic Therapy failed to cure gonorrhoea
In 2016, the first case of pharyngeal gonorrhoea that did not respond to dual therapy (azithromycin & ceftriaxone) was identified in the UK.
November 2016- The Science and Technology Select Committee warns of AMR
The Science and Technology Select Committee in the UK, warns about the dangers and implications of the rise of antimicrobial resistance.
April 2017 – WHO Priority Pathogens List
The World Health Organization has created and released a list of the highest priority current AMR pathogens across the world.
January 2018 – Gonorrhoea strain more resistant
The first strain with high resistance to both azithromycin and ceftriaxone has been identified in the UK and has now spread globally.
November 2020 – World Antimicrobial Awareness Week
The World Antibiotic Awareness Week has been renamed to World Antimicrobial Awareness Week and is now held on each November of the year. The slogan for the event has now been changed to ‘’antimicrobials: handle with care.’’
January 2021- Oxford University AMR Research
The University of Oxford receives a 100 million grant to tackle antimicrobial resistance and emphasizes the need for more research on the issue. The university drew comparisons between the well-researched vaccine fields and how the investments and research in the field have led to the quick development of the COVID-19 vaccine and the lack of funding and research for antimicrobial resistance.
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