The WHO Collaborating Centre on Global Health Histories, which is supported by the Wellcome Trust, has produced a series of seminars in association with the WHO HQ, WHO Regional Offices, WHO Country Offices and national governments which look at the issue of antimicrobial (antibiotic) resistance, and why this remains such a difficult topic to tackle.
The seminars can be viewed and/or listened to here:
Global Health Histories Seminar 102: Strengthening Universal Health Coverage for the fight against Anti-Microbial Resistance
Location: Colombo, Sri Lanka
Speakers; Professor Sanjoy Bhattacharya, Director, Centre
for Global Health Histories (CGHH), University of York; Dr Lakshmi Somatunga,
Deputy Director-General, Medical Services(I), Ministry of Health, Sri Lanka;
Dr Sunil De Alwis, Deputy Director-General, Education, Training &
Research, Ministry of Health, Sri Lanka (Presented by Dr Dilantha
Dharmagunawardena); Dr Suranga Dolamulla, Wellcome Trust Senior Research
Fellow, University of York, Director of Tertiary care Services, Ministry of
Health, Sri Lanka; Dr Kushlani Jayatilleke, Consultant Microbiologist, Sri
Jayewardenapura General Hospital, Sri Lanka; Dr BVSH Beneragama, Deputy
Director-General/ Laboratory Services, Ministry of Health, Sri Lanka; Dr Anil
Jasinghe, Deputy Director-General, National Hospital of Sri Lanka
Global Health History Seminar 116: Antimicrobial Resistance
Location: Aarhus University, Denmark
Speakers: Dr Janis K. Lazdins Helds (formerly TDR/WHO, Coordinator
Product Development and Evaluation for drugs, diagnostics and vaccines for
neglected tropical diseases) and Professor Jens Seeberg (Dept. of Anthropology,
Aarhus University)
Global Health Histories Seminar 137: Anti-microbial Resistance in South Asia: Challenges & Possibilities
Location: Jawaharlal Nehru University, Delhi, India
Speaker(s): Panellists: Professor Nandini Sharma (Maulana Azad Medical College, New Delhi), Dr Klara Tisocki (WHO South-East Asia Regional Office), Dr Suranga Dolamulla (University of York, UK and Ministry of Health, Sri Lanka), Dr Sirenda Vong, (WHO South-East Asia Regional Office)
Location: Colombo, Sri Lanka
Speaker(s): Dr B. V. S. H. Benaragama (Deputy
Director-General, Laboratory Services and the National focal point for
combating antimicrobial resistance, Ministry of Health, Sri Lanka), Professor
Vajira H. W. Dissanayake (Chair and Professor of Anatomy, University of Colombo
and Chairman, Commonwealth Centre for Digital Health), Dr Suranga Dolamulla
(Wellcome Trust Senior Research Fellow, University of York and Ministry of
Health, Sri Lanka)
Department of Health Products Policy and Standards, Medicines and Health Products, WHO. This whole scenario is really threatening our ability to treat common infectious diseases. It is resulting in prolonged illness, disability and death,” agrees Dr Lakshmi Somatunga of the Ministry of Health, Sri Lanka. It is also affecting animals and the environment.
And yet, like climate change, AMR is yet to be tackled
effectively. It is more complex than simply telling practitioners or patients
to stop overusing or misusing their medication. “Most people agree there is a
problem but some have huge economic stakes invested in active denial of the
facts; and political will to act locally is very slow to emerge in ways that
mirror global power imbalances,” says Professor Jens Seeberg of Aarhus
University (where he specialises in the field of anthropology of global health
and antimicrobial resistance).
Access to and quality of antibiotics worldwide
Most of the global guidelines about antibiotic use and overuse originated from richer WHO members. In lower-income countries, the problem is more about access to medication, and the quality of that medication when it is available. “The key and most important thing that can be done is ensuring good-quality antibiotics, with a secure supply chain,” Tisocki says.
Dolamulla describes “two different scenarios of antibiotic production” for different parts of the world. “The developing world was really suffering without antibiotics and many actors, especially international organisations, supported antibiotic production for needy countries. But the technology transfer did not happen as expected. Sri Lanka was one of the countries that flagged this up with the WHO, wanting help to produce and prepare drugs in-country; other countries wanted a mix of imports and support.” Commercial pharmaceutical companies approached a number of countries, with the aim of moving into this market. “The Indian government was about to pay a very high amount of money as a royalty fee to a penicillin-producing company when one of the people conducting a WHO economic assessment mentioned that going ahead with a WHO-supported plant would be a good option for India rather than going ahead with the private firms. Even Sri Lanka did not get external organisational support for its antibiotics production plan, and had difficulties buying medicine from the world market because of the foreign currency exchange crisis.”
Today, antimicrobial use is strikingly different across the world. Tisocki outlines the WHO’s three categories [https://adoptaware.org/]: Access, Watch and Reserve. The Access category covers the antibiotics of choice for the 25 most common infections, which are recommended to be ‘available at all times, affordable and quality-assured’. “In a number of countries (Netherlands, Brazil etc) over 90 per cent of the antibiotics being used come from this list,” she explains. “In countries like Bangladesh, India and China it’s about 30 per cent.” About 40 per cent of the antibiotics used in those countries come instead from the Watch category, which are recommended ‘only for specific, limited indications’ and about 10 to 20 per cent from the ‘Reserve’ group, which the WHO states ‘should only be used as a last resort when all other antibiotics have failed’.
It’s also the case that many people, especially poorer
people, access antibiotics without a prescription. Seeberg describes the way
this happens in India. “Buying antibiotics over the counter from outlets that
may or may not be formally registered is not an exception: it is common
practice. Chemist shops function as de facto primary care practitioners and the
booming Indian pharmaceutical industry pushes drug sales through any outlet,
whether or not formal medical expertise is present. Antibiotics are everywhere
and consumed for a wide range of ailments, only some of which may be attributed
to some kind of bacterial infection. Everyday practitioners, with or without
medical qualifications, receive visits of dozens of pharmaceutical sales agents
who provide the only available kind of information about these drugs.” This is
compounded, Seeberg adds, by the fact that many doctors also prescribe
unnecessary drugs. “Quality can also be a big problem,” Tisocki adds. “If you
have a sub-standard, poorly manufactured antibiotic which has only 60 per cent
of the active ingredient, that’s most likely going to breed resistance.
Anti-infectives and anti-parasitics are the most common in this category. It’s
a big business; everyone buys a lot of antibiotics so criminals are very happy
to move into it.”
The rise of AMR
Antimicrobials were initially hailed as a ‘magic bullet’ by the WHO when they were first introduced, with a programme with UNICEF in 1949. “Even then, though, people were aware of the potential risk and the possibility of resistance,” Dolamulla points out. Some diseases that were first tackled effectively, such as gonorrhoea, started to see a lapse in recovery rates. “In 1952 the WHO noted the proliferation of new drugs and potential AMR, and instructed members to take measures to prevent this.”
Dr Janis K Lazdins-Helds (formerly TDR/WHO, Coordinator Product Development and Evaluation for drugs, diagnostics and vaccines for the neglected tropical disease, and now an independent consultant) explains some of the complex mechanisms by which resistance develops. “It’s a natural phenomenon. Most antibiotics are derived from bacteria, and those bacteria develop mechanisms to protect themselves. So that is what's called ‘intrinsically related’ antimicrobial resistance: the natural defence mechanism.
“Then in clinical settings, there is ‘acquired’ resistance, where organisms lose their susceptibility to antimicrobials. They do so either because their own genes mutate, or because they acquire genetic material from other bacteria. This genetic information sometimes carries elements for different drugs, so a multi-resistant component comes in. The other aspect that is not usually highlighted is these things are both transmitted vertically, within a given species, and horizontally between different species.”
In addition, he adds, biocides (detergents) and heavy metals can also induce resistance. And resistance can be expressed in different ways. “Basically each antibiotic has a different mechanism of action or different target in the bacterial cell, and that target or that mechanism can be altered by the genetic information that the bacteria acquire.”
Moving on from the mechanism, he also explains the way AMR spreads. “In the human microbiome, our intestinal environment contains all kind of bacterial elements. These include some AMR components, but normally they do not proliferate. If you are submitted to antibiotic therapy you are changing the microbial environment in your gut, and then the bacteria with the resistance component have an advantage and start proliferating. Those bacteria then end up in the environment, are transmitted horizontally into other materials and enhance the pool of bacteria which have that form of AMR: and that again is acquired by humans. It can easily be carried from one environment to another. To illustrate this: if a healthy individual goes to a country where there's a high prevalence of antimicrobial resistance, they will probably be carrying these bacteria in their intestinal environment when they return home. Nothing will happen if they are not exposed to antibiotic treatment. But if they are, these bacteria will enhance.”
Lazdins sums up: “When addressing AMR you have to think
about two things: First, the root determinants of antimicrobial resistance,
which are basically determined by the microbiology of the process, the ecology
of the microorganisms and the epidemiology (meaning how it’s acquired by the
host and environment); and second, the morbidity and mortality that are the
expression of AMR.”
AMR’s wide-ranging effects
This mix of unprescribed drugs, substandard medication, misuse and overuse has played a particularly huge role in the development of drug-resistant tuberculosis (TB), Seeberg points out. “Unless the market for antibiotics is regulated through a strengthening of the public sector and based on some kind of control with the marketing strategies of the pharmaceutical sector, this problem will continue. Controlling drug-resistant tuberculosis should be considered within the broader framework of controlling AMR.” This is especially urgent because there are two new drugs that are effective in tackling drug-resistant TB, and these may not remain effective if the wider issues of AMR are not addressed.
The effects of AMR do not stop with human beings. Farm
animals are routinely fed antibiotics, often in large quantities.
[https://www.who.int/news/item/07-11-2017-stop-using-antibiotics-in-healthy-animals-to-prevent-the-spread-of-antibiotic-resistance]
“If you look at the bigger picture, 70 per cent of the production of
antibiotics in the world goes to the animal sector, to protect them from infection.
A lot of people in the agricultural sector prefer to give antibiotics before an infection happens. They are using antibiotics, not for the right reasons, and it
is also one reason why AMR is on the rise,” says Dr Sirenda Vong, (WHO South
East Asia Regional Office) There is also a severe effect on the environment because residual material and ingredients can percolate into the water during the manufacturing process and then be discharged into the surroundings.
Shaping international opposition to AMR
As Dolamulla flags up, this issue has been a concern for many years now; and the WHO first passed resolutions about it in 1998. “We have 20 years of this, addressing policies, but what is interesting from the perspective of history is the context in which these things have been put across, over the years.” The first resolution focused on issues like education, research and control. In the next few years, the emphasis shifted to containment, within the context of health security and epidemic alerts. In 2007 the attention was on the rational use of medicines. Seven years later, the focus returned to the original one. The resulting 2015 WHO global action plan [https://www.who.int/antimicrobial-resistance/global-action-plan/en/] has five strategic objectives: improving awareness and understanding; strengthening knowledge through surveillance and research; reducing the incidence of infection; optimising the use of antimicrobials; and developing a comprehensive case for sustainable investment. “This is very similar to what was said back in 1998,” Dolamulla says.
At the same time, there is an important historical context which has to be taken into account. Professor Sanjoy Bhattacharya, Director of the Centre for Global Health Histories (CGHH), University of York has looked at the earlier history of the drugs – the point at which antimicrobials were being hailed as a ‘magic bullet’, despite reservations – and made some surprising findings. “What is very striking is that initially, the WHO didn’t have any essential lists of medicines. If you follow the money in relation to these lists, what you find out is stunning; and it’s something that historians have ignored till now. In the 1950s and 1960s, it was countries like India and Ceylon/Sri Lanka which were actually funding the development of new departments within the WHO headquarters and the WHO regional office. It was Asian money – not American or Western European money – which was creating changes within the WHO although it wasn’t politic for anyone on either side to talk about this.”
Bhattacharya explains why this particularly important when
it comes to combating AMR. “There was wide-ranging political support within
South-East Asia not only for creating the creating essential lists but also
for introducing antibiotics into that list for all sorts of treatments.
Medication including antibiotics was seen as a right and a mark of equity.”
The need for information and surveillance
There is also another sticking-point when it comes to defeating AMR resistance: the need to know exactly what is being used where, in a field where much consumption is simply unmonitored. Vong sums it up. “Surveillance is essential because you need to show the data to see where you are, and in order for countries to advocate for more funding and resources to combat AMR. How do you sell that idea of the rise of antibiotics to the public, or to other professionals, when you don’t know how many people are dying of it and you don’t have that data? We come up with something about microbiology, but how many people understand that concept? It’s easy to talk about raising awareness but how you do it is more complex.” It’s also necessary to collate this information across different countries and sectors, covering the use in all fields. “This is a global issue. The [WHO] global AMR surveillance system is essentially an IT platform to collect all data across the world. We want to measure trends, and to know if the data we have is accurate. We also want to measure the use of antibiotics and establish whether reducing antibiotic use or using antibiotics better has an impact on AMR.”
However, at the moment, Vong explains, that data simply
isn’t available. “There is some from the US, Europe and Thailand. But when you come to a country
like India or Sri Lanka and ask for data on AMR, where do you start? The level
of resistance to one particular antibiotic?” This is compounded even further by
the specific nature of the data that’s needed. “AMR surveillance data is
complex to collect and to analyse. How many bacteria are we dealing with? How
many antibiotics are we dealing with? And what type of infection are we dealing
with – is it blood, is it urinary, is it respiratory? Analysing one dosage
against another is very complex.”
Ways forward
Some specialists are exploring ways to make antibiotic use much more customised, through gene sequencing, and give patients exactly the appropriate treatment. “The conventional culture techniques will help us pick up that dominant organism but it doesn’t give the bigger picture of the surrounding colony of microorganisms; so you kill the dominant organism but the ulcer continues. You try other antibiotics and so on, and this goes on and on. This kind of thing actually contributes to perpetuating the scourge of AMR,” explains Professor Vajira H.W. Dissanayake, Professor of Anatomy and Genetics, Faculty of Medicine, University of Colombo, Immediate Past President Commonwealth Medical Association, and Chairman, Commonwealth Centre for Digital Health'. “Alternatively, you can completely customise different ways of treating the patient. You completely analyse the microbiome and do the bioinformatics analysis which gives you the entire drug-resistance pattern. So you’ve got your set of organisms which are based on the sequence, you identify what is resistant to what and then you can also determine which drug to give which patient.” Others are starting to look at how the resistance could be reduced within a drug that has become ineffective, by eliminating or silencing the genetic element which has made this happen.
Much of the current focus is on finding new drugs to replace
ones that are now becoming ineffective. But for one thing, that does not tackle
the problem of AMR in itself: it just shifts it into the future. In any case,
drug development on this front is not going ahead as fast as it might be. “Not
only are large pharmaceutical companies reluctant to take forward innovative
molecules/approaches: more concerningly, they are exiting antibiotic research
altogether,” says Lazdins “This is partly because the drugs they do develop
would not necessarily be used, Dolamulla adds. “We are asking them to produce
new antibiotics exactly to attack resistant organisms. The US Centers for
Disease Control (CDC) has said something very remarkable: that this antibiotic
stewardship is good for public health but the production of new antibiotics is not
good for drug companies as there is a long lead time (20 years) and low return on the initial investment. So
basically it’s not the best from a business perspective.”
Radhika Holmström is a Wellcome Trust-funded writer and communications specialist working with the WHO Global Health Histories project at the University of York.
