Professor David Graham of Newcastle University explains the vital role of sanitation in reducing the spread of AMR.
Antimicrobial resistance (AMR) is mainly caused by the misuse and overuse of antimicrobials, threatening the use of these as an important treatment method for a range of infections. A lack of access to clean water and sanitation, and inadequate wastewater infrastructure further drives the spread of microbes, including drug-resistant microbes. It has been reported that without effective antibiotics, human life expectancy is predicted to fall by 20 years. Urgent action is required. It was estimated that 1.27 million additional deaths occurred in 2019 due to bacterial AMR and this death toll could rise to as many as 10 million annual deaths by 2050.
Newcastle University scientists have developed new testing methods to facilitate a more accurate way of quantifying the spread of AMR. Here, Health Europa speaks to study co-author, Professor David Graham of Newcastle University, about the benefits of these new testing methods, and how an efficient wastewater infrastructure is key to preventing the spread of drug-resistant microbes.
To begin, how does a lack of access to clean water and sanitation increase the spread of AMR?
There are two important factors that we found to be most relative to AMR spread: one is using too many antibiotics and the other is not using antibiotics in an appropriate and balanced way. Most places in the world use antibiotics for their intended purpose, but in some places, there is a tendency to overuse the most important antibiotics. That causes an opportunity for AMR to spread, both within and outside of clinics.
We have looked at several countries, and every place which tightened antibiotic use have still had antibiotic resistance if they do not have an adequate waste management system. When an antibiotic is taken, it resides in your gut and acts as a strong selector for organisms that are tolerant or resistant to the antibiotic. The antibiotic kills most of the organisms, and we know this because the patient’s health improves. But unfortunately, the microbial world is diverse, and a sub-fraction of strains will be resistant due to random mutations or having acquired resistance through genetic exchange.
This means that when an antibiotic is taken, even if it is taken in a prudent way, more resistant organisms are expelled in your faecal matter than if you are not taking the antibiotic. Therefore, if you do not manage the wastewater being discharged, the resistant organisms can contaminate the receiving water.
This is a big problem in the developing world as approximately 75% of the world do not have sewers or an adequate wastewater management system. In places where you do not have waste treatment, those resistant genes and bacteria that are in faeces get put into the water and are spread through the water supply. We know this to be true due to a study we conducted on animal feedlots in the US, where we compared how antibiotic use varied from lot to lot.
We had one suite of lots that were organic and did not use antibiotics. There was another set of lots that used antibiotics purely for therapeutic purposes. For these lots, if there was a sick animal, the animal would be taken out of the herd and would be treated with antibiotics and then returned. The third lot used antibiotics as growth promotors, which was a preventative effort to try and stop the animals from causing an epidemic within the animal community, as the animals were in such close contact.
We found that the animal operations in the organic lot had about 1,000 to 10,000 times less AMR, in this case, genes and bacteria in their wastewater, compared to the therapeutic and growth promotor lots. The feedlots using antibiotics therapeutically versus preventatively did not vary very much, which appears to be very counterintuitive. The problem is that in an animal feedlot, animals are not intrinsically sanitary. If you put the previously infected animal, that has taken antibiotics, back into the herd, it defecates and contaminates the water of the rest of the herd so the whole herd gets this resistance.
We looked further at this idea by looking at the movement of individuals along the Ganges in India and found that the same phenomenon was happening there. If there is no waste management, then even minimal levels of antibiotic use were demonstrated to cause a community-scale spread. Appropriate sanitation and maintaining high quality water is the best way to prevent the spread of AMR across the environment.
We conducted a study in New Delhi where we looked at this on the city-scale and found the places with the highest levels of resistance were at the downstream end of the city (sewage drains downhill), and the areas at the upstream end of the city had lower levels of resistance. Wealth is not an important factor to levels of antibiotic resistance; it is where you reside relative to where sewage drains in an inadequate drainage system. We found that if you were downstream, you were getting exposed to the resistance that was in the water of people upstream. It is a lack of sanitation which is causing the spread of resistance; the resistance is spread through the environment.
Can you explain how wastewater has been used as a tool to guide healthcare decisions during the pandemic?
Monitoring wastewater tells you about what is present in the community, as one’s faecal matter is a mirror of each individual’s health. The benefit of this is that you can get an approximation of the whole community. Measuring waste has been a method used for many years, and has great community health protection value.
Now, if we are looking at an individual person, for example, the first person who stepped into the UK with the Omicron variant, wastewater will not capture that individual event. What the wastewater will tell you is whether places such as Swindon or Nottingham have higher levels of the Omicron variant. This kind of information is helpful if you are making strategic health decisions and deciding on regional quarantines. Wastewater information is not always as valuable as people might think for the COVID-19 situation but from my perspective, COVID has been useful in increasing awareness about faecal matter mirroring an individual’s health. Drug resistance is ideally suited to wastewater monitoring because it tells us about the diversity of resistance and the spatial demographics.
The important thing currently is putting this information about the environment into a preventative care plan. As the UK has had clean water for 70 years, it is challenging to get healthcare professionals to take a One Health approach rather than an individualistic approach to this problem.
If you are a physician in the UK, you do not see the problems that a physician may see in Thailand or Myanmar. We do a lot of work in India and Bangladesh, and 80% of their job is dealing with waterborne or foodborne infectious disease, compared to countries like the US and the UK where such is generally much lower. This is because high-income countries have significantly reduced waterborne disease spread. Places like the UK are comparatively lucky, but this is not the case for about 80% of the world. Therefore, a more global perspective is needed to reduce the environmental spread of AMR.
What happens in one side of the world does not happen in isolation. When it comes to the environmental spread of disease, anything that moves, like wildlife and water, can pick up the disease and carry it somewhere else. When it comes to AMR, especially waterborne AMR, that can spread through the environment, through the water.
What are the key challenges facing the healthcare sector in preventing the spread of AMR infection?
The biggest challenge is increasing awareness that disease still can spread through the environment. Each disease is different, and each infection pathway is different. For example, when it comes to carbapenem-resistant enteric bacteria (CRE), like Klebsiella, when somebody contracts this disease in a low-income country, they defecate into the environment, it goes down a sewer drain, and due to a lack of infrastructure, it then can go into a river that exposes other people and wildlife who then travel themselves. Every time that somebody travels, the resistance spreads to and within that new location.
There needs to be a greater emphasis on educating physicians and public health professionals about the importance of environmental pathways, and what needs to be realised is that most of the world does not have infrastructure like the UK.
You and your colleagues have successfully trialled two new qPCR assays to detect transmissible AMR. Can you outline your DNA-based testing method and explain the benefits of this?
One of the things to do with environmental monitoring, is when it comes to something like COVID, you have got a specific target. For example, scientists have developed ways of detecting and screening different variants, despite the variants not differing too much away from the original strain.
With AMR, the same type of phenotypic resistance can happen based on hundreds of different genes. Also, you do not know when measuring a gene in an environmental sample, that resistance is there. What it does mean is that antibiotic use was probably somewhere upstream of that location. You do not know if you have got real resistance until you have got a resistant infection where a treatment fails.
That is the problem, we can measure genes, and other sorts of indicators in the environment, but it does not explicitly tell you that you are going to get resistance. What measuring the environment tells us is that there is a greater potential of AMR if the concentration of these resistant genes is high.
The question is how do you go about measuring hundreds of different genes that could potentially be your problem? We looked for genetic surrogates and microbial surrogates that allow us to tell where resistance potential is greatest. It tells you that there is a greater probability of transmissible resistance in one place versus another.
There has been an assay that has been around since 2008, which is based on class one integron genes. An integron can be defined as a mobile gene cassette, composed of a gene-encoding integrase, which hold the genes within. This assay has been known for many years as being a surrogate for detecting the potential for resistance because they are frequently the carrier of resistant genes.
The problem is that integrons are also natural, so they are not always related to infectious disease. It is not specific to resistance except empirically, you frequently find higher levels of these integron cassettes in places with higher levels of resistance. When we started looking at what was genetically associated with integron cassettes, we often found that they had nothing in them. This means that the marker that we were using to find the presence of resistance, was actually just the shell of a way that resistance could move.
The old quantitative assay did not distinguish between an empty shell and when the integron is carrying the resistant genes. We found places where 70% of the integrons in an environment are just shells. To get around this problem we redesigned using a series of gene probes that have been around for years, that targeted these integrons. Our new assays were an improved version of those probes, making the assays more exact to identify the integrons that come from clinically intact environments. One probe that we have quantifies integrons that are actively carrying resistance genes, and the other probe is one that tells you that the integron is an empty shell.
By making this more precise, we can use integrons more accurately as a surrogate for resistance. People used the old gene assays and trusted them, but we found as we were using them in different contexts, we were sometimes getting results that did not make sense, especially false positives for AMR. The value of the new probes is that they are specific, they tell you whether the integron is going to be associated with transmission, but we are also correlating these to the abundance of actual resistant strains.
The shell could re-acquire a gene, but early evidence suggests that these shells do not re-acquire genes very easily unless they get back into a bacterial host. We suspect this is because a shell needs energy for it to be able to perform a function, and if it is out there in the environment, or it is in a bacterium that does not have resistance exposure, the shell is just an inert entity.
The new paper of ours explains that these empty cassettes exist, in some places there is a high abundance of them, and they do not exist equally in each place. This tells us which places within the ecological network have a greater versus lesser chance of transmission.
What steps should be taken at a policy level to avoid the worst-case scenario of 10 million annual deaths by 2050?
First, we need to have much more control and rational use of antimicrobial agents, and in the UK that has already happened, and it is happening in other parts of the world. Despite this being the right decision, without control of environmental exposures of AMR, the problem cannot be solved. The solution requires an integrated policy, in the clinic and in the environment, following a One Health type of approach.
The whole premise behind One Health is that you protect the individual, the animal, and the food and the environment in which people live, and then through that collective preventative umbrella higher quality environment is created at the microscopic and macroscopic scale. Through doing that, the way healthcare is thought about is changed to a much more integrated and holistic way.
Another problem arises with the semantics of the words used in the medical and environmental worlds. For example, the word transmission is used in three different ways. Also, when I am talking about the environment, it could mean the chair you are sat on, the country that you live in, or the river that you walk by. Each person will take different terms in slightly different ways, although we are working to unify the terminology, especially transmission and spread.
For the worst-case scenario to be avoided, there should be a common approach used by medical professionals, as well as the definition of terms being decided on objectively. Sanitation is key in this and is the best solution to prevent the spread of AMR across the world. This is what people must understand, even if sanitation and water infrastructure are not problems for those in high-income countries, the spread of AMR is a problem which affects the globe.
Professor David Graham
Professor of Ecosystems Engineering