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The State Of: Antimicrobial Resistance

Antimicrobial resistance (AMR) is one of the most pressing public health threats we will face in our lifetimes. In fact, in 2019, almost 5 million deaths worldwide were associated with bacterial AMR, with this number only growing.

In this feature, we take a look at the State Of the bacterial AMR field, looking at the past, the present and the future to give you a comprehensive overview of the research landscape.

The past

The introduction of antibiotics into global healthcare systems was widely regarded as a medical marvel, saving millions of lives that would have otherwise likely succumbed to infection. Antibiotics remain a key tool in modern healthcare, but their usage is not as simple as it once seemed.

Before the discovery of modern antibiotics, ancient civilizations used various natural substances to treat infections. An infamous example of this is the use of mouldy bread to treat infected wounds in Ancient Egypt. But it wasn’t until 1928 that the first modern antibiotic, penicillin, was discovered by Scottish bacteriologist Alexander Fleming. The compound was first successfully purified 12 year later, by Howard Florey and Ernst Boris Chain. These scientific landmarks earned Fleming, Florey and Chain the Nobel Prize in Physiology or Medicine in 1945, with penicillin first being mass produced in the same decade. The impact was almost immediate, with penicillin significantly reducing mortality rates from bacterial infections among troops towards the end of World War II.

The success of penicillin saw the rise of several new antibiotics, including streptomycin – one of the first effective antibiotics for Tuberculosis. In what is widely regarded as the ‘golden age of discovery’, the next three decades saw the development, and entry into the clinic, of more than half of the drugs that are used to treat infections to this day. Further refinement of these medicines continued beyond the 1980s, but the discovery of truly novel antimicrobials began to stagnate towards the end of the 20th century.

Enter the problem of resistance. Once hailed as miracle drugs, it became clear towards the end of the 20th century that overuse of antibiotics was a growing health concern. As highlighted in Fleming’s Nobel Lecture, pathogens obtaining resistance to the drugs was always a possibility. As antibiotics became more widely available, and their use became common in both medicinal and agricultural settings, the challenge of AMR grew. With a remarkable ability to evolve and adapt, bacteria developed mechanisms to survive exposure to antibiotics (Figure 1), and misuse and overuse of these drugs led to the emergence of multi-drug resistance. Whilst it’s easy to assume that this is primarily due to use in a healthcare setting, in reality, agricultural practices contribute heavily to the threat of resistance. 80% of antibiotics used in America are found in agriculture, 70% of which are designated as medically important.

Figure 1. Image describing AMR mechanisms employed by pathogens. Taken from Centers for Disease Control and Prevention.

Antimicrobial resistance is now recognised as a global health threat by the World Health Organization (WHO), with millions of deaths associated with this crisis every year – a number that is only growing. Scientists are continuing to research novel medicines and new treatment strategies, but with the drug discovery process still long and treacherous, the real results will come from antibiotic stewardship initiatives and One Health approaches to science, health and agriculture.

The present

Antimicrobial resistance has been an ongoing problem for decades, but in recent years substantial efforts have been made to understand and address this challenge. Let’s take a look at some key papers from the last year.

The burden of antimicrobial resistance in the Americas in 2019: a cross-country systematic analysis (Antimicrobial Resistance Collaborators, 2023) – AMR is a global health threat, and this paper published in August last year explores the burden of AMR in the Americas in 2019. The authors estimate over half a million deaths were associated in some way with AMR.

Antimicrobial resistance surveillance in Europe 2023 – 2021 data (Stockholm: European Centre for Disease Prevention and Control and World Health Organization, 2023)– Similar to the above, this report published last year explores AMR trends across Central Asia and Europe during 2021.

The burden of bacterial antimicrobial resistance in the WHO African region in 2019: a cross-country systematic analysis (Antimicrobial Resistance Collaborators) – Additionally, this comprehensive report assesses AMR trends in Africa during 2019, presenting a further international analysis of this health crisis.

Measuring the global response to antimicrobial resistance, 2020–21: a systematic governance analysis of 114 countries (Patel et al., 2023) – This report published in early 2023 assesses publicly available national action plans from over 100 countries to elucidate how different nations are tackling AMR.

Real-time genomic surveillance for enhanced control of infectious diseases and antimicrobial resistance (Struelens et al., 2024) – This article, published just last month, calls for the use of real-time genomic surveillance to track and control resistant bacteria, following the successful use of these strategies in the COVID-19 pandemic.

Tackling the threat of antimicrobial resistance in neonates and children: outcomes from the first WHO-convened Paediatric Drug Optimisation exercise for antibiotics (Bamford et al., 2024) – This article, published in April 2024, details the results of the WHO’s first Paediatric Drug Optimisation exercise, which aims to prioritise antibiotics for use in paediatrics due to the risk of AMR affecting young people.

Antimicrobial resistance and the great divide: inequity in priorities and agendas between the Global North and the Global South threatens global mitigation of antimicrobial resistance (Mendelson et al., 2024) – This Viewpoint article, published earlier this year, explores discrepancies in the way AMR is tackled globally, and calls for better consistency, prioritisation and the reallocation of global resources to mitigate the spread of the problem.

Antimicrobial resistance crisis: could artificial intelligence be the solution? (Lie et al., 2024) – As is the case in many fields, experts are looking for ways to use AI to curb AMR. This report explores how machine learning could be used to discover and develop new drugs in a quicker way than using traditional methods.

From FLG

Last year, we had the pleasure of interviewing Professor Craig MacLean (Professor of Evolution and Microbiology, University of Oxford) about the challenges in the AMR field. Below are some snippets from the conversation.

FLG: What is the ‘big challenge’ in your field? 

Craig: AMR is a very complex and multifaceted problem, and there are many challenges. I’m going to focus on challenges that are related to genomics.

A long-standing challenge has been predicting AMR from genome sequences. There’s been a fundamental revolution in clinical microbiology that has been driven by increased sequencing of pathogen isolates, and just how much easier that has become. There’s a lot of interest in the ability to directly predict AMR from genome sequences, because that has a lot of potential as a diagnostic tool.

Where this is most important is in something like tuberculosis (TB). TB remains one of the leading causes of death due to infectious disease; mortality due to TB is greater than the combination of HIV plus malaria. When people have TB infections, measuring the resistance of the isolates phenotypically takes a few weeks, whereas by genome, theoretically, it can be done within days, maybe hours. That’s the clearest example of where there’s going to be a huge clinical benefit from being able to predict resistance directly from genome sequence.

But that’s not really what I work on, so I want to focus on another challenge, the challenge of understanding the bigger genomic context of AMR. Traditionally, people in the AMR field focus really strongly on a small number of genes that clearly have big effects on antibiotic resistance. The prototypical example of this would be horizontally transferred beta-lactamases that confer high levels of resistance to a whole range of beta-lactam antibiotics that are very important in the clinic. But what I want to focus on is understanding the bigger genomic context of AMR.

For example, how does the rest of the genome influence the ability of bacteria to acquire resistance genes? This is going to tell us something about how evolvable bacteria are, how readily they acquire new resistance genes and how the rest of the genome moderates the pleiotropic effects of those resistance genes. Resistance genes often have all kinds of important phenotypic effects on traits like competitive ability and fitness. If we understand how the rest of the genome moderates those, we can potentially identify the Achilles’ heel of antibiotic resistant bacteria. Say, for example, if we identify that there’s a gene X, and it makes a particular resistance gene really costly under these conditions, then we could potentially modulate the conditions in the clinic so that resistance becomes costlier to the bacteria.

FLG: Why should people care about this challenge? 

Craig: I think AMR is going to be one of the biggest challenges that humanity will face in the 21st century. For most of human history, infectious disease has been a leading cause of death, and we’re tragically in a situation where we’re heading towards that being the case again. Resistant infections are predicted, by some models, to be the leading cause of human mortality by the mid-21st century, on par with cancer. The tragedy that those overall numbers hide is that if we compare AMR and cancer, we know that the risk of cancer increases exponentially with age, meaning that people who died from cancer are predominantly the elderly. But with resistant infections, it’s actually two groups who are very much at risk; the elderly and immunocompromised, but also children who are under the age of five. I think that this is something that often gets missed when people just look at the overall numbers.

Read the full interview here.

The future

As resistance continues to grow, it is predicted that the number of deaths attributable to AMR will increase to over 10 million a year by 2050, overtaking cancer as a leading cause of mortality worldwide. Alongside the obvious health impacts, the World Bank estimates that the rise of AMR could lead to severe economic impact, disproportionately affecting developing countries.

The rising number of deaths due to AMR are largely due to infections caused by the ESKAPE pathogensEnterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., and sometimes Escherichia coli. These bacteria are increasingly becoming multi-drug resistant, causing severe hospital-acquired infections in many cases. Global efforts to stop the spread of these resistant pathogens and to combat infections caused by them are underway, but they remain a threat.

Of course, the discovery and development of novel drugs, not yet subject to resistance, would be a seemingly perfect avenue to tackle this problem. But drug discovery is a long and difficult process, requiring an investment of billions of dollars and years of research. In fact, the WHO previously reported that the pipeline for new antibiotic development had stagnated. In addition to this, developing new antibiotics doesn’t solve the problem of pathogens eventually developing resistance to these new drugs.

These concerns have led to a search for alternative treatments to tackle bacterial infections. Although not a new idea, phage therapy is at the forefront of a lot of current research. This treatment uses bacteriophages, viruses that infect and kill bacteria, to target particular strains of bacteria, eliminating harmful pathogens while leaving beneficial bacteria and, crucially, human cells unharmed. A number of clinical trials are already investigating the efficacy and safety of these therapies, and a review published earlier this year showed that 80% of individuals treated with phage therapies in the last two decades showed improvement.

However, treatment is not the only avenue to tackle resistance. Crucially, we must work to ensure that the spread of bacterial infections is curbed. This is particularly important in hospital settings, where vulnerable patients can acquire life-threatening infections, and in regions where limited access to amenities, such as clean water, contributes to the spread of pathogens. The WHO has made several recommendations to tackle these issues. At the centre of this is the One Health approach, which aims to face AMR on a global scale, in a multidisciplinary manner, to ensure that all sectors do their part to ensure the mitigation of the spread of resistant bacteria.

More on these topics

AMR / Antibiotics / Microbiology