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20th October 2023
Air pollution contains particulate matter that can carry antibiotic resistance genes, which have been found to accelerate microbial threats to human health. Here, Rod Tucker considers the extent to which air pollution could serve as a primary vector and driving force behind the increasing levels of global antibiotic resistance.
There‘s no doubt that global antibiotic resistance represents a major health challenge and is responsible for a huge number of deaths. For example, in a systematic review looking at the global burden of bacterial antimicrobial resistance in 2019, the authors estimated there were 4.95 million associated deaths.
In addition, data published in 2018 from the European Centre for Disease Prevention and Control estimated that around 33,000 people die each year in the in the European Union and European Economic Area as a direct consequence of infections with antibiotic-resistant bacteria.
Although antibiotic resistance represents the failure of a particular drug, there are a number of underlying factors responsible. Perhaps the greatest risk comes from interconnected human, animal and environmental habitats that are likely to contribute towards the emergence, evolution and spread of antibiotic resistance. In fact, resistance emerges as a result of the local confluence that occurs when bacteria colonise different human and animal hosts, enabling the spread of antibiotic resistant genes.
In response to the global rise in antibiotic resistance, countries have introduced antimicrobial stewardship programmes. Such initiatives represent a coordinated approach to promote the appropriate use of antimicrobials and reduce both microbial resistance and the spread of infections caused by multidrug-resistant organisms.
Antimicrobial stewardship programmes are predicated on the notion that antibiotic use per se, is associated with the development of resistance. However, simply controlling usage may not be an effective means of reducing the rate at which resistance develops.
This was highlighted in a 2018 analysis of the factors driving global antimicrobial resistance. It found that reducing antibiotic consumption would be unlikely to control antimicrobial resistance because the spread of resistant strains and resistance genes seemed to be the most important contributory factor.
So, if this is case, what are the most likely vectors of resistant genes?
In 2018, Chinese researchers profiled the relative abundances of 30 antibiotic resistance genes (ARGs) in urban air carried in particulate matter. They found that urban air is being polluted by ARGs and different cities are challenged with varying health risks due to airborne ARG exposure.
Moreover, fine particulate matter, with a diameter of 2.5 μm or less (i.e. PM2·5), is easily inhaled and therefore serves to increase the intake of airborne ARGs.
But to what extent is air pollution and the carriage of ARGs actually responsible for the spread of resistance?
A more recent study by Chinese researchers tried to answer this question. Writing in the journal Lancet Planetary Health, the team provided the first global estimates of antibiotic resistance and burden of premature deaths attributable to antibiotic resistance resulting from PM2·5 pollution.
They used data from multiple sources and included a number of potential confounders, such as levels of air pollution, antibiotic use, sanitation services, climate, year, and region, from a total of 116 countries collected between 2000 and 2018.
Using raw antibiotic-resistance data on nine pathogens and 43 types of antibiotic agents, the team identified significant global correlations between PM2·5 and antibiotic resistance (R2= 0.42 – 0.76, p<0.0001). Furthermore, these correlations appeared to strengthen over time.
The researchers also estimated that antibiotic resistance derived from PM2·5 led to an estimated 0.48 million premature deaths and 18.2 million years of life lost in 2018 worldwide. In other words, with a positive and robust association between PM2·5 and antibiotic resistance, the findings implied that globally, air pollution, and in particular PM2·5, was an important driving factor.
While the findings from the Lancet Planetary Health study are intriguing, this was an ecological study, which is more suited to the generation of hypotheses, and the finding of an association between air pollution and antibiotic resistance is not necessarily causal.
The authors of the paper also acknowledge some limitations. For instance, several low- and middle-income countries – the likes of which are most affected by antibiotic resistance – did not provide pathogen and antibiotic data.
In addition, the unrestricted use of antibiotics in animal farming was not examined in the study, which is a potentially important determinant of resistance in countries that also tend to have higher air pollution levels.
Finally, the authors also state that ‘some factors could be almost as important as PM2·5 in contributing to antibiotic resistance’. This is another way of stating the obvious: there are lots of other possible factors that could account for the observed association. As information on such data was unavailable, it could not be included in the statistical models.
While it is possible that air pollution is a factor linked to increased levels of antibiotic resistance, in the absence of experimental evidence to support this premise, it remains yet another factor to be considered and addressed, if possible, in the global fight to reduce the adverse outcomes associated with increased antibiotic resistance.
7th July 2023
Patients with higher prior antibiotic use are more likely to experience severe Covid-19 outcomes after infection, including hospitalisation and death, a new study led by the University of Manchester has shown.
When infected with Covid-19, the chances of dying from complications due to Covid-19 is 1.34 times higher in patients with the most exposure to antibiotics than those without antibiotic exposure.
The research, published in The Lancet‘s eClinicalMedicine, is the first to explore how the severity of Covid-19 is affected by prior antibiotic use.
The UK team of scientists behind the work say the findings should act as a warning against the overuse of antibiotics.
Using the NHS OpenSAFELY platform, which enabled the researchers to look at electronic health records across primary and secondary care, the team examined data from 670,000 patients infected with Covid-19 between February 2020 and December 2021. The patients were reviewed for Covid-19 outcomes and divided into five groups based on the frequency with which they had taken antibiotics three years prior to infection.
Each group was further split based on the number of different antibiotics a patient used, giving the researchers an understanding of how the frequency and diversity of antibiotic use affect the body’s response to a Covid-19 infection. Of the sample, 98,420 patients were admitted to hospitals, 22,660 died, and 55 unique antibiotics were prescribed.
Patients with more frequent antibiotic exposure in the past three years were more likely to experience severe Covid-19 outcomes, including admission to hospital and death within 30 days.
The odds of being hospitalised due to a Covid-19 infection were 1.8 times higher for those with the highest history of antibiotic use and the most diversity of antibiotic use. Using a range of antibiotics was more likely to be associated with Covid-19 hospital admission, and using a larger range of antibiotic types was associated with more severe consequences of Covid-19 upon hospital admission.
Professor Tjeerd van Staa, a principal investigator from the University of Manchester, said: ‘Our study has provided evidence that patients with high prior antibiotic use were more likely to experience severe Covid-19 outcomes. In addition, we also found an association between the number of different prior antibiotic types and Covid-19 related hospital admission.’
The researchers suggest this may be because frequent antibiotic use can increase the likelihood of patients being infected with viruses or bacteria, leading to an increased susceptibility to adverse consequences of infection.
Professor Van Staa added: ‘The literature shows that antibiotic treatment might alter gut microbiota, which can impact metabolic and immune function. While in most situations gut microbiota will recover after stopping an antibiotic course, frequent antibiotic use may affect the resilience of gut microbiomes more seriously.’
The researchers suggest that antibiotic guidelines should outline the possible adverse consequences of the overuse of antibiotics, and personalised patient leaflets could highlight these risks and the risks of the patient’s bacteria developing resistance to antibiotics.
Co-principal investigator Dr Victoria Palin from the University of Manchester said: ‘Common infection guidelines in England, as developed by the National Institute for Health and Care Excellence, focus on the treatment of the first infection episode. They do not provide guidance around repeated antibiotic use and a patient’s risk of developing resistance.’
She added: ‘There needs to be more awareness of the impact of long-term antibiotic exposure and its adverse outcomes. We would discourage regular and indiscriminate prescribing of these drugs for self-limiting infections.’
This article was originally published by our sister publication Nursing in Practice.
30th May 2023
Using a machine learning approach, researchers have identified a molecule that can potentially treat infections due to Acinetobacter baumannii – a common cause of a nosocomial infections in hospitals that is often multi-drug resistant.
Acinetobacter baumannii (A. baumannii) is an opportunistic, nosocomial pathogen and one of the six most important multi-drug-resistant microorganisms in hospitals worldwide. The organism has become particularly troublesome in hospitals due to its ability to survive for prolonged periods of time and an innate resistance to both desiccation and disinfectants. As a result, there is a growing and urgent need to develop novel antibiotics to overcome drug-resistant organisms.
One novel approach to drug discovery is the use of machine learning algorithms. The value of this strategy was recently utilised to predict molecules with broad-spectrum antibacterial activity against Escherichia coli.
But could this approach also be used to develop narrow-spectrum antibiotics, targeting specific organisms, given how this strategy has at least two potential advantages? Firstly, the spread of resistance is less likely with narrow-spectrum antibiotics because of less selection pressures. Secondly, narrow-spectrum agents do not cause dysbiosis – that is disruption to the microbiome – during treatment.
In a recent study published in Nature Chemical Biology, US and Canadian researchers used machine learning to focus their attention on identifying antibiotics targeting A. baumannii. The team screened approximately 7,500 molecules, looking at the ability of these agents to inhibit the growth of the organism in vitro. The search identified a set of 480 active molecules – those able to inhibit growth of A. baumannii. Further filtering using the algorithm reduced this to 240 molecules that were structurally different to existing antibiotics.
Ultimately, one compound, abaucin, demonstrated a very potent inhibitory action. Looking at its possible mechanism of action, the team identified how the drug appeared to interfere with lipoprotein trafficking, which is involved in development of an organism’s outer membrane and an intrinsic antibiotic resistance factor.
To examine the potential value of abaucin, researchers then tested the activity of the molecule against 41 known strains of A. baumannii. Surprisingly, they found it able to overcome all intrinsic and acquired resistance mechanisms in these 41 isolates. Furthermore, in a mouse model of an infection due to A. baumannii, abaucin proved to be an effective treatment.
The team also found that abaucin displayed minimal growth inhibitory activity against 51 human commensal species isolates, suggesting that it was unlikely to cause dysbiosis during treatment.
Looking forward, the researchers suggested once a novel antibacterial agent had been identified, machine learning models could be trained to examine the growth inhibition of a pathogen of interest, as well as the potential toxicity of the drug to mammalian cells.
In addition, with more high-quality datasets on which to train machine learning models, the researchers felt that this approach could become widely employed in future to more efficiently identify structurally and functionally effective new antibacterial agents.
28th April 2023
Antimicrobial resistance is one of the biggest challenges for hospitals and healthcare services to deliver safe and effective healthcare. A 2018 survey estimated that around 33,000 people die each year in the in the European Union and European Economic Area as a direct consequence of an infection due to bacteria resistant to antibiotics.
In 2020, the European Hospital and Healthcare Federation (HOPE) published a position paper on antimicrobial resistance (AMR). Here, the organisation’s chief executive Pascal Garel provides an update and offers his recommendations on prevention policies, fostering the One Health Approach and promoting the development of new antimicrobials.
The ‘One Health’ perspective of the European Commission’s Action Plan provides an opportunity for stakeholders representing different sectors and constituencies to provide expert inputs for improving the implementation of the Plan. This includes experts from the human health, animal health and food production, and environmental disciplines.
Hospital and healthcare providers are clearly important in this regard. Healthcare environments are places where antimicrobial-resistant bacteria emerge and spread, but also where actions can be particularly effective for preventing future outbreaks and ensuring prudent use of antimicrobials.
Other important voices involved in fighting antimicrobial resistance are: medical professionals, nurses, hospital and community pharmacists, students, infection prevention and control specialists and carers. In addition, it is relevant to include organisations with a broader remit, such as public health, health education and research-focused organisations, and those promoting solutions such as rapid diagnostics, vaccines and alternative medicines for veterinary uses.
It is not sufficient to rely exclusively on Member States’ own funding, given that there is a marked north-south and west-east gradient regarding consumption of antimicrobials and AMR prevalence. Moreover, the development and implementation of National Action Plans (NAPs) has been uneven. Over half of the Member States have no action plans, or have plans that are no longer valid or about to expire. A lack of access to funding – including the possibility to combine different funding programmes and projects to complement one another in the longer term – and of other resources, such as laboratory capacities, healthcare resources, infection prevention and control specialists, are often cited as main reasons.
Supplementing national budgets with a dedicated EU-AMR funding mechanism is necessary to close these gaps. Using the European Structural and Investment Funds and providing technical assistance through the European Structural Reform Support Programme is also needed.
The impact of Covid-19 on healthcare budgets and on the ability of hospitals and healthcare facilities to operate effectively should not be underestimated. Health worker shortages, supply issues related to PPE, and persistent budget cuts are stretching many health institutions to the limit. While it is clear that the size and immediacy of the AMR threat will necessitate the diversion of some national and institutional funds, this is not sufficient to solve the issue and could indeed exert a negative impact on other crucial areas, such as the ability to guarantee continuity of care during health security crises.
A key barrier is the need to develop, adopt and fund a long-term vision that exceeds the political mandates of most national governments and hence complicates endorsement and implementation of NAPs. Therefore, the role of the European Commission and of international groups – such as the WHO, G7 and G20 – is vital in avoiding AMR slipping off the political radar and any policies under development merely following a one-sided approach.
More tangible guidance on devising impactful antimicrobial resistance frameworks is required. This goes beyond listing actions to include dedicated funding pooled from different policy areas. Increased political instability and societal divisions – reared also by ‘fake news’ and conspiracy theories online – further complicate this task as decision-makers are primarily focused on short-term quick wins.
The pandemic crisis demonstrated that action can be taken quickly when needed: the problem being that the new EU health budget is the product of a reactive rather than proactive approach. However, the AMR threat is as serious as that of Covid-19, and concrete steps are required to move towards a European Health Union. These steps are driven by values of solidarity, with the European Centre for Disease Prevention and Control given an enhanced health security framework and extended powers for surveillance, preparedness and response planning.
There is growing awareness at national level that certain health-related problems – such as AMR – require enduring and targeted commitment as well as dedicated financial, human and technological resources. The EU One Health Network should be replicated at national level in recognition of the urgency.
We work in partnership with stakeholders representing the agricultural and veterinary areas as part of an AMR Stakeholder Network originally created under the European Health Policy Platform. The One Health perspective draws attention to the interlinkages between excessive uses of antibiotics in food production, animal husbandry and human health, among other things contributing to the rise of non-communicable chronic diseases and the growing threat of infectious diseases and pandemics, both, in turn, requiring functional antibiotic drugs to combat them.
Without being able to speak for the agricultural and veterinary sector, HOPE endorsed the AMR Stakeholder Network’s Roadmap. EU rules banning the routine use of antibiotics and restricting preventative uses to special circumstances are in place. However, the bigger change needed is moving away from highly intensive livestock farming systems involving both routine and excessive use of antibiotics. Available options include altering production systems by reducing stocking density, different breeds and so on; exploring alternatives to antibiotics; and antibiotic stewardship programmes.
Establishing an EU-wide antibiotic formulary is not feasible given the different healthcare needs, patient profiles and antimicrobial prescribing practices at national and regional levels. However, the existing EU Guidelines for the prudent use of antimicrobials in human health should be expanded. This could include more concrete information aimed at different professions. Some harmonised guidance for specific antimicrobials commonly used in all countries could contribute to better prescribing and handling in all Member States.
Member States developing stewardship programmes within the hospital sector, but also covering community and long-term care settings, with the help of EU funding ensures that healthcare professionals are well prepared to tackle multi-drug resistance. This would also facilitate cross-border cooperation and better ensure that AMR protocols are adhered to during serious health crises such as the Covid-19 pandemic.
A multidisciplinary approach to the implementation of stewardship programmes encourages mutual learning and transfer of expertise. This is more effective than offering lectures or encouraging self-study.
Antimicrobial stewardship should be part of educational curricula to inform students and trainees of antimicrobial resistance and encourage prudent use from the outset.
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