"We don’t know which transmission routes are crucial."

Many countries currently support research on the development and spread of antimicrobial resistance (AMR). Which knowledge gaps still need to be closed, and what can this research add to the fight against AMR? We discuss these questions with Jean-Yves Madec, newly-elected member of the NRP 72 Steering Committee. The molecular microbiologist is Research Director at the French Agency for Food, Environmental and Health Safety (Anses) and coordinates all scientific activities dealing with surveillance, reference and research on AMR at the agency.

The French government has recently launched a research programme on AMR, which has a very similar scope to the Swiss programme NRP 72. One central aim of both is to better understand the development and spread of AMR across humans, animals and the environment. Where do you see the biggest knowledge gaps in this regard?

We all know that it is absolutely necessary to consider the spread of resistance across all sectors. This One Health-approach brought science a big step forward, and it is very good to see that policymakers support more research. When you look at reviews addressing the topic, you see extensive diagrams in which everything is connected with everything else. Which is quite right. But all these forests of arrows don’t give you a clear picture of the main driving forces.

And now the task is to show not just that things are connected, but also how they are connected?

Indeed, we don't really know if some intersectoral transmission pathways have a greater effect on the global AMR burden than others. We need to quantify the effects. Here I see many gaps, which can be closed in the coming years. For example, Dutch colleagues only recently published a modelling study on ESBL (1) transmission across all sectors. The outcome is that human-to-human transmission of ESBL accounts for more than 60 percent of all human carriage of ESBL. And the contributions of the other sectors – food, contact with livestock, pets etc. – account for the rest.

Can such quantifications serve as a basis for concrete measures?

You can look at this data in different ways, depending on what you want to make it say, as is the case with a large amount of data in this area. We have learnt a lot about the evolution of AMR, but when it comes to taking action, we still don’t know which transmission routes in and between sectors are crucial if we want to interrupt the whole cycle.

Does the One-Health approach want too much then?

Let’s just say it sometimes runs the risk of people losing themselves in the more global and evolutionary aspects and forgetting the driving forces at the more local or more sectoral level. But it’s nonetheless absolutely crucial. Things are interrelated, and we’ll only solve the problem if we take this into account.

You mention the more local level when it comes to action. To what extent is research on the spread of AMR within all these national programmes of practical importance beyond individual countries?

Many results are generalisable, but their practical relevance depends on regional conditions. For example, when the MRSA (2) crisis occurred in the Netherlands in 2004, researchers provided general evidence that MRSA can be transmitted from pigs to humans. Thus, being a pig farmer is a risk factor for getting MRSA. But this knowledge did not have the same impact in the Netherlands and in France.

Why?

Because the prevalence of MRSA in pigs was, and is, quite low in France. Despite the fact that MRSA transmits the same way as in the Netherlands, not much action on MRSA was taken in France. This means, you have to think globally from a scientific point of view, but nevertheless you have to act locally.

You say the One Health approach still lacks quantified evidence about the importance of single transmission routes. Does it have an effect on real-life action?

The One Health approach has already had a huge practical impact. Though many things are not yet precisely quantified, the evidence that the different sectors are connected is there. This is the reason why the farmers and the vets joined the efforts against AMR. Unlike medical doctors, they don’t have to deal directly with treatment failures. But they joined the the effort because they use antibiotics and know that this contributes to the global burden of AMR.

In fact, farming and veterinary medicine in France have achieved a substantial reduction in the use of antibiotics over the past years.

That’s precisely due to our success in showing and explaining how the use of antibiotics in animals leads to resistance, and how this can transmit from the animal and the environmental sector to humans and back. What is nice in France is that also medical doctors are now using the success achieved by veterinarians to try and convince their own colleagues.

And the professionals in the different sectors talk to each other, search for solutions, agree on which way to go?

We have indeed been highly successful in bringing all the different professional communities together to discuss the same topic. But I think we are at a critical point now. Because the farmers and vets have done a lot, we need to be clear about our next targets going forward. At the same time, to be honest, I'm not sure that we have scientific evidence that decreasing the prevalence of AMR in animals has had any impact on the situation for humans.

You mean, it is questionable if it was worth the effort?

No, that can be ruled out. Actually, I think everyone would like to take the effort further. We can’t go back to the massive use of antibiotics seen in the past. Neither can we aim for zero use in animals, because they need to be treated, too. What is important now is to put everything into a One Health perspective, where it becomes clear what additional efforts lead to what results. And where we also see which efforts are still needed in other sectors, not least in human medicine. For example, we know that the French population use antibiotics a lot more than the Dutch population. So the challenge for the years to come is to uphold the interaction between the different professional communities. And again, a better quantification of the effects of intersectoral transmission pathways will help a lot to that end.

Do you expect scientific breakthroughs in the coming years, of the kind that would fundamentally enhance our capabilities to fight AMR?

We have already witnessed fundamental advances, mostly methodological ones with the establishment of rapid and affordable DNA sequencing technologies. Thanks to these advances, we have gained access to massive quantities of genomic data and established new approaches to monitoring and diagnosing AMR. But the new opportunities are mainly being used in industrialised western countries and not in Southeast Asia or Africa, where the burden of AMR is much higher. In my view, achieving game changing results will depend on whether those countries can benefit from research outcomes to the same extent.

1. Extended-spectrum beta-lactamases (ESBLs) are enzymes that can be formed by bacteria and lead to resistance to several classes of antibiotics.
2. MRSA (methicillin-resistant Staphylococcus aureus) is an antibiotic-resistant type of sthaphylococci.