The global threat of antimicrobial resistance
Antimicrobial resistance (AMR) is a major and serious problem. It represents possibly the greatest global crisis in public health today, akin to climate change as the top environmental problem.
ANTIMICROBIAL resistance is resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it. Resistant microorganisms (including bacteria, fungi, viruses and parasites) are able to withstand attack by antimicrobial drugs, such as antibacterial drugs (e.g., antibiotics), antifungals, antivirals and antimalarials, so that standard treatments become ineffective and infections persist, increasing the risk of spread to others.1
Resistance by bacteria and other microbes to antibiotics and other medicines may be a natural process, as the disease-causing microbes evolve through time in response to the medicines. However, the rate of resistance is accelerated and the scope of resistance broadened by several factors: the inappropriate use of antibiotics, due to inappropriate prescribing and dispensing; inappropriate marketing methods and sales promotion; lack of awareness among patients; the inappropriate and widespread use of antibiotics in the animal husbandry and agriculture sector, which passes on resistant microbes to humans; the spread of resistance through the environment; and the existence of certain genes that specialise in accelerating and spreading resistance among bacteria, thus greatly increasing the rate and spread of resistance to many species of bacteria that cause diseases.
AMR is now a global crisis, with many pathogens becoming resistant to many antibiotics. As leading public health officials and senior scientists have warned, we are now entering a post-antibiotic world, in which it is increasingly difficult to treat simple ailments and dangerous diseases. The incidence of multidrug resistance has risen significantly, and for a few diseases there is almost no cure left. In 2012, then World Health Organisation (WHO) Director-General Dr Margaret Chan warned that every antibiotic ever developed was at risk of becoming useless. ‘A post-antibiotic era means in effect an end to modern medicine as we know it. Things as common as strep throat or a child’s scratched knee could once again kill.’ The Chief Medical Officer of the United Kingdom, Dame Sally Davies, warned in 2013 of a ‘catastrophe’ of AMR being so widespread that we would be back to a 19th-century situation of a pre-antibiotic era when many diseases could not be treated.
Recent information on the extent of resistance
A good description of the extent of the AMR crisis has been given by WHO in its Fact Sheets on AMR. The following is a summary of the WHO findings as at January 2018:2
• Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi.
• Patients with infections caused by drug-resistant bacteria are at increased risk of worse clinical outcomes and death compared with patients infected with non-resistant strains of the same bacteria. They also consume more healthcare resources than patients having non-resistant strains of the same bacteria.
• There are high proportions of antibiotic resistance in bacteria that cause common infections (e.g., urinary tract infections, pneumonia, bloodstream infections) in all regions of the world.
• Resistance of Klebsiella pneumoniae (common intestinal bacterium that can cause life-threatening infections) to a last-resort treatment (carbapenem antibiotics) has spread to all regions. In some countries, because of resistance, carbapenem antibiotics do not work in more than half the people treated for K. pneumoniae infections. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, and infections in newborns and intensive care unit patients.
• Resistance in Escherichia coli to a widely used medicine for treating urinary tract infections (fluoroquinolone antibiotics) is very widespread. This treatment is now ineffective in over half of patients in countries in many parts of the world.
• A high percentage of hospital-acquired infections are caused by highly resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Gram-negative bacteria. People with MRSA are 64% more likely to die than those with a non-resistant form of S. aureus, which is a common cause of severe infections in the community and hospitals.
• In 2016, there were 490,000 new cases of multidrug-resistant tuberculosis (MDR-TB). Only a quarter of these were detected and reported. Extensively drug-resistant tuberculosis (XDR-TB) has been identified in 121 countries. MDR-TB requires treatment courses that are much longer and less effective than those for non-resistant TB. Among new TB cases in 2016, 4.1% were MDR-TB (19% for those previously treated for TB). About 6.2% of people with MDR-TB have XDR-TB.
• As of July 2016, resistance to first-line treatment for P. falciparum malaria (artemisinin-based combination therapies or ACTs) was confirmed in five countries (Cambodia, Laos, Myanmar, Thailand, Vietnam) of the Greater Mekong subregion. Patients with artemisinin-resistant infections recover if they are treated with an ACT containing an effective partner drug. However, along the Cambodia-Thailand border, P. falciparum has become resistant to almost all available antimalarial medicines. The spread or emergence of multidrug resistance, including resistance to ACTs, in other regions could jeopardise important recent gains in malaria control.
• Treatment failures due to resistance to treatments of last resort for gonorrhoea (third-generation cephalosporin antibiotics) have been confirmed in at least 10 countries. The new updated WHO guidelines for gonorrhoea do not recommend quinolones (a class of antibiotic) due to widespread high levels of resistance. Gonorrhoea may soon become untreatable as no vaccines or new drugs are in development.
• In 2012, WHO reported a gradual increase in resistance to HIV drugs, albeit not reaching critical levels. Since then, further increases in resistance to first-line treatment drugs have been reported. In 2010, 7% of people starting antiretroviral therapy (ART) in developing countries and 10-20% in developed countries had drug-resistant HIV. In some countries, resistance of 15% or more is reported for those starting HIV treatment, and up to 40% among those restarting treatment. Those who have HIV resistant to first-line treatment require second- and third-line regimens but these are three and 18 times more expensive respectively than first-line drugs.
The global response
The WHA Global Action Plan and other developments
WHO’s World Health Assembly (WHA) in May 2015 adopted the Global Action Plan (GAP) on Antimicrobial Resistance. It has five objectives: (i) to use medicines properly in human and animal health; (ii) reduce infection by sanitation, hygiene and infection prevention measures; (iii) strengthen surveillance and research; (iv) educate the public as well as doctors, veterinarians and farmers on proper use of antibiotics; and (v) increase investment in developing new medicines, diagnostic tools and vaccines.
Implementation of the GAP at global and national levels will be a good start in the long battle against AMR. It is important to recognise the conditions and challenges faced by developing countries and assist them to address these challenges in order to facilitate their implementation of the plan.
The WHA resolution (WHA68.7) adopting the GAP requested WHO member states to submit national action plans (NAPs) within two years, i.e., by May 2017. WHO, the UN Food and Agriculture Organisation (FAO) and the World Organisation for Animal Health (OIE) have produced a manual for preparing the NAPs.3
As of April 2017, 67 countries had completed their national action plans and 62 others were in the process of doing so, according to a WHO secretariat report.4 Almost all the NAPs reflect the One Health approach, with a multisectoral coordination group and actions planned across health, agriculture and other sectors. According to WHO: ‘The challenge now is to implement plans, sustain action and ensure that essential priority actions are incorporated into relevant plans and budgets.’
WHO has also carried out the following: (i) established the Global Antimicrobial Surveillance System (GLASS), with 43 countries enrolled or in the process of doing so; (ii) developed a list of critically important antimicrobials for human medicine (WHO CIA List), with the latest version in 2016; (iii) published in November 2017 a set of guidelines on the use in food-producing animals of the antimicrobials included in the list, aimed at preserving their effectiveness and protecting public health; (iv) published in 2017 a set of guidelines on infection prevention and control at the national and acute healthcare facility level; (v) published in 2016 global guidelines on the prevention of surgical site infection; (vi) published an updated version of the WHO model list of essential medicines in 2017, with an antibiotic chapter offering guidance on management of major infective syndromes; and (vii) issued a list of priority antibiotic-resistant bacterial pathogens where new medicines are most urgently needed, to guide the priority for research and development (R&D) of new antibiotics.
Pursuant to a decision in resolution WHA68.7, WHO is also developing, in consultation with member states and relevant partners, ‘options for establishing a global development and stewardship framework to support the development, control, distribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions, while preserving existing antimicrobial medicines and promoting affordable access to existing and new antimicrobial medicines and diagnostic tools, taking into account the needs of all countries, and in line with the global action plan on AMR’. The document is still under preparation.5 A draft of the framework has been prepared by the WHO secretariat. It is important for developing countries to take an active role in the consultations with WHO to develop this framework.
The UN General Assembly high-level event and political declaration on AMR
Another landmark development at the global level on AMR was the adoption on 21 September 2016 of a political declaration by heads of state and government at a high-level event on AMR. It was subsequently formally adopted by the United Nations General Assembly.
Many political leaders and ministers spoke at the event on the need to fight the AMR crisis. The political declaration recognised that antibiotic resistance is the ‘greatest and most urgent global risk’ and that ‘due to AMR many 20th century achievements are being gravely challenged, particularly the reduction in illness and death from infectious diseases…’. This is the first-ever statement by the heads of all the countries that recognise the AMR crisis and in which they pledge to take action.
The then UN Secretary-General Ban Ki-moon said that AMR has become one of the biggest threats to global health. ‘All around the world, many common infections are becoming resistant to the antimicrobial medicines used to treat them, resulting in longer illnesses and more deaths. At the same time, not enough new antimicrobial drugs, especially antibiotics, are being developed to replace older and increasingly ineffective ones.’
The heads of three international agencies, WHO, FAO and the OIE, made speeches and also issued a joint statement signifying their joint efforts to address AMR. The WHO Director-General Margaret Chan warned that ‘AMR poses a fundamental threat to human health, development and security’. Referring to the declaration, she said ‘the commitments made today must now be translated into swift, effective actions … We are running out of time.’
The declaration stressed the need for developing countries to obtain financial resources. It also stressed that ‘affordability and access to existing and new antimicrobial medicines, vaccines and diagnostics should be a global priority’.
On the need for innovation, the declaration recognised the importance of delinking the cost of investment in R&D from the price and volume of sales so as to facilitate equitable and affordable access to new medicines, diagnostic tools and vaccines.
The declaration established a task force of agencies (co-chaired by WHO and the UN Secretary-General’s office) which would provide guidance for global action on AMR, and requested the UN Secretary-General to report on progress of implementation of the declaration and to make further recommendations.
In 2017, the Interagency Coordination Group (IACG) was established by the UN Secretary-General to follow up on the declaration. It was made up of individual experts (many drawn from health ministries) and representatives of UN and other international organisations. The final report of the IACG was submitted in April 2019 to the UN Secretary-General, who will present his own report to the UN General Assembly in 2019. (See following article.)
The need for developing-country involvement
It is to be expected that the developed countries will take the lead in the global fight against AMR. This is due to the greater availability of financial resources, and higher levels of scientific knowledge, research capability and technology as well as institutional and organisational capabilities including in the healthcare sector. Thus much of the global progress in the fight against AMR, in science, technology, surveillance, regulations and discovery of new antimicrobials, is expected to take place first in the developed countries.
However, the developing countries will also have to play a central role in the global battle against AMR, since it is in these countries that the majority of the world population reside, that there is the highest number (and in some cases highest incidence) of people suffering from drug-resistant diseases, and that pathogens with the genes specialising in spreading resistance have mainly been found in patients. Moreover, in an increasingly globalised world with a high degree of travel and trade, there can be the easy spread of drug-resistant bacteria and diseases.
Therefore, the special needs and interests of the developing countries have to be given the highest priority in the global fight against AMR if we are to make adequate progress.
Developing-country awareness of the AMR crisis
Political leaders and public health officials in developing countries are becoming more aware of the AMR crisis.
At the summit meeting of the Group of 77 and China, which has 130 developing-country member states, held in Santa Cruz (Bolivia) in May 2014, the political leaders of the Group adopted a declaration which included the following paragraph 66:
‘We are concerned about the increasing problem of antimicrobial resistance to existing drugs, including those against TB and malaria. As a result, increasing numbers of patients, especially in developing countries, face the prospect of dying from preventable and/or treatable diseases. We urge the international health authorities and organisations, especially WHO, to take urgent action and to work together upon request with developing countries that do not have adequate resources to address this problem.’
In May 2017, the Non-Aligned Movement (NAM)’s health ministers and senior officials met on the sidelines of the World Health Assembly. The NAM ministerial declaration they issued referred to AMR as follows: ‘We express great concern on the spread of antimicrobial drug resistance and its potential massive threats to global public health achievements and the urgent need for global action to address this threat and, welcoming the political declaration of the high-level meeting of the UN General Assembly on antimicrobial resistance and progress made in implementing resolution WHA68.7 on Global Action Plan on Antimicrobial Resistance; and the crucial need to support Member States with technical assistance to develop their national plan on antimicrobial resistance in response to the Global Action Plan.’6 NAM is a movement of more than 100 non-aligned countries, most of them developing countries, which works mainly within the UN. It is significant that such an umbrella organisation of so many developing countries called for urgent global action to address AMR and expressed the crucial need to support its member states with technical assistance to develop their national AMR plans.
The health ministers of WHO’s South-East Asia Region, at a WHO regional workshop in Jaipur (India) in September 2011, adopted the Jaipur Declaration on AMR, which included the following: ‘We the Health Ministers of SEAsia Region … recognise it is imperative that national governments accord utmost priority to this neglected problem, to preserve efficacy of anti-microbial agents in our fight against microbial diseases.’ It was followed by 18 action points.
And as mentioned above, in May 2015, the World Health Assembly, of which the majority of members are from developing countries, adopted the Global Action Plan on AMR, with a commitment that national action plans would be drawn up by all countries within two years. However, in most developing countries, the public is still lacking knowledge and awareness of the threat of AMR, while coordinated and systematic action is also at only a beginning stage. Therefore, much more has to be done.
Impact of AMR in developing countries
People in developing countries will be most affected by the AMR crisis. AMR is estimated by the UK-sponsored Review on Antimicrobial Resistance, in a 2014 report, to globally cause 700,000 deaths annually at present (and this is a low estimate).7 The number of annual deaths attributable to AMR is projected to rise to 10 million in 2050. Of these deaths, it is projected that 390,000 will be in Europe, 317,000 in North America, 22,000 in Oceania, 4.7 million in Asia, 4.2 million in Africa and 392,000 in Latin America.
For most diseases the majority of people affected by AMR are in developing countries. The Review on Antimicrobial Resistance concludes that ‘countries that already have high malaria, HIV or TB rates are likely to particularly suffer as resistance to current treatments increases’.8 Particular countries at risk include India, Nigeria and Indonesia (malaria) and Russia (TB), and Africa will suffer greatly as the HIV and TB co-morbidity is likely to get worse.
The Review also estimates that 300 million people are expected to die prematurely because of drug resistance over the next 35 years (i.e., 2015 to 2050) and world GDP will be 2% to 3.5% lower than it otherwise would be in 2050. Between now and 2050 the world can expect to lose $60-100 trillion of economic output if AMR is not tackled. (By 2030, world GDP will be 1.4% smaller, with over 100 million people having died prematurely.) Countries from the Organisation for Economic Cooperation and Development (OECD, the club of rich nations) are expected to have $20-35 trillion in cumulative loss of output by 2050; which means that about $40-65 trillion or two-thirds of the losses will be borne by non-OECD countries.
The case of tuberculosis is illustrative. In a 2016 report, the Review on Antimicrobial Resistance found that of ‘the 10 million deaths that might be associated with drug resistance each year by 2050, around a quarter will come from drug-resistant strains of TB’.9 Most of these anticipated cases and deaths from resistant TB will be from developing countries, although TB is also affecting several developed countries.
The majority of people affected by increasing resistance to drugs treating malaria and to the first-line treatments for HIV/AIDS are also from developing countries. Pathogens that are increasingly resistant to powerful antibiotics (E. coli, K. pneumoniae, S. aureus, Salmonella, Shigella, gonorrhoea) are prevalent in developing countries.
Policymakers and the public in developing countries should therefore recognise that the AMR crisis is mainly taking place in their countries and that they have to give the highest priority to addressing it. At the same time, the international community has to pay special attention to the needs of developing countries and to assist them in addressing the AMR crisis.
Genes accelerating resistance found in developing countries
In recent years, there has been the discovery of at least two types of genes (NDM-1 and MCR-1) that have the characteristic of being able to make bacteria highly resistant to known drugs and to also spread from one species of bacteria to other species through horizontal gene transfer. Bacteria containing these genes were first found in developing countries, and their presence is now confirmed in many other countries. The discoveries of NDM-1 and MCR-1 add urgency to the task of addressing antimicrobial resistance.
The NDM-1 gene has the ability to alter bacteria and make them highly resistant to drugs. In 2010, two types of bacteria (E. coli and K. pneumoniae) were found to host this gene. Most of the initial cases were found in South Asian countries. It has since spread to many countries. The gene has been found to jump among various species of bacteria at superfast speed, making more species of bacteria drug-resistant. NDM-1 has now been found in over 20 species of bacteria. The gene makes the bacteria highly resistant to all known drugs except two, including colistin.
In 2015, scientists found another gene, MCR-1, which creates resistance to colistin, a powerful antibiotic used as a last resort to treat infections when other medicines do not work. The gene also has the characteristic of being able to move easily from one strain of bacteria to other species of bacteria. Yi-Yun Liu and colleagues published a paper in The Lancet Infectious Diseases journal in 201610 revealing they found the MCR-1 gene in pigs at slaughter that they tested, chicken and pork being retailed and hospital patients. The scientists found the gene in 166 out of 804 pigs at slaughter that they tested, 78 of 523 samples of chicken and pork being retailed, and in 16 of 1,322 hospital patients. The study indicates there is a chain in the spread of resistance from the use of colistin in livestock feed to colistin resistance in slaughtered animals, in food and in human beings. Colistin is part of a category of antibiotics known as polymyxins. Previously they had not been widely used in humans due to their toxic side-effects, but they have recently become a last-resort treatment when other antibiotics do not work because of resistance.
One of the authors of the study, Prof. Jian-Hua Liu from South China Agricultural University, was quoted by The Guardian as saying these are extremely worrying results, which reveal the emergence of the first polymyxin resistance gene that is readily passed between common bacteria such as E. coli and K. pneumoniae. This suggests that ‘the progression from extensive drug resistance to pan-drug resistance is inevitable’, added Liu. Extensive resistance is when a bacterium is resistant to many drugs, while pan-drug resistance indicates resistance to all drugs.
Another of the paper’s co-authors, Prof. Timothy Walsh from the University of Cardiff, told the BBC: ‘All key players are now in place to make the post-antibiotic world a reality. If MCR-1 becomes global, which is a case of when and not if, and the gene aligns itself with other antibiotic resistance genes, which is inevitable, then we will have very likely reached the start of the post-antibiotic era. At that point, if a patient is seriously ill, say with E. coli, then there is virtually nothing you can do.’
A major reason for the emergence and spread of the gene is suspected to be the heavy use of colistin to feed livestock to promote their growth. In February 2016, The Lancet published a comment from scientists that ‘we must take the call to curtail the use of polymyxins (including colistin) in agriculture to the highest levels of government or face more patients for whom we need to say, “Sorry there is nothing I can do to cure your infection.”’ Other antibiotics that are used by human beings should also be prohibited or heavily restricted in the livestock sector, especially if they are used as growth promoters.
The 2016 paper mentioned that besides China, the MCR-1 gene had also been found in Malaysia and Denmark. Since then, the gene has also been discovered in bacterial samples in many other countries, including Thailand, Laos, Brazil, Egypt, Italy, Spain, England and Wales, the Netherlands, Algeria, Portugal and Canada.
Martin Khor is Advisor to the Third World Network. The above is extracted from his paper The Global Threat of Antimicrobial Resistance and the Challenges and Needs of Developing Countries (TWN Series on Antimicrobial Resistance, No. 1, 2019). The paper is a revised and updated version of a background paper used as speaking notes by the author in a panel discussion during the UN General Assembly high-level event on antimicrobial resistance at the UN in New York on 21 September 2016.
1 World Health Organisation (WHO), 2015. Fact Sheet on Antimicrobial Resistance.
2 WHO, 2018. Fact Sheet on Antimicrobial Resistance, January 2018.
3 WHO, FAO, OIE, 2016. Antimicrobial resistance: a manual for preparing national action plans.
4 WHO, 2017. Antimicrobial resistance: Report by the Secretariat (Document A70/12, dated 10 April 2017).
5 See WHO, 2017. Antimicrobial resistance: Report by the Secretariat (Document A70/12, 10 April 2017), paragraph 18 for a report on the progress of the framework.
6 See South Centre News on AMR No. 4, 6 September 2017.
7 Review on Antimicrobial Resistance, 2014. Antimicrobial resistance: Tackling a crisis for the health and wealth of nations, pages 5, 13.
8 Ibid., page 9.
9 Review on Antimicrobial Resistance, 2016. Tackling drug-resistant infections globally: Final report and recommendations.
10 Yi-Yun Liu et al., 2016. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study, The Lancet Infectious Diseases, 2016, 16: 161-68.
*Third World Resurgence No. 339/340, 2019, pp 25-29