The challenges of implementing responsible antibiotic use and how to overcome them

Ladies and Gentlemen,
it is a great honor to be able to speak to you today at this beautiful venue, and I would like to thank the German Embassy and the PEW Charitable Trust for their invitation to this important and very timely event.

As the president of the Robert Koch Institute, the issue of antimicrobial resistance, or AMR, has been one of my main concerns over the past years. For those of you who are not quite familiar with our institute, the RKI can best be described as the German counterpart to the CDC. We act as scientific advisors to the national government and the ministry of health and we consult on a broad range of topics: from vaccination to zoonotic infections, and from health monitoring to chronic diseases. In this role, we also monitor and work on AMR, which has been a growing concern over the past twenty years.

Many of you will be familiar with the consequences of antimicrobial resistance, but I find that it is always worthwhile to repeat just how far-reaching the effect of AMR already is, and how much worse we can expect the situation to get if we do not act quickly and decisively. A conservative estimate for the current burden of AMR is that around 700,000 people die every year as a consequence of drug-resistant bacterial infections. Without a concerted international effort to stem the tide, it is likely that this number will increase dramatically in the future. The recently released AMR Review, which was commissioned by the UK government, predicts that by 2050 this number may rise to as many as 10 million deaths per year, surpassing cancer as one of the most frequent causes of death. How accurate this forecast is, is of course hard to say. As Niels Bohr - the famous physicist - is said to once have observed; “prediction is very difficult, especially about the future”. Yet, irrespective of the precise death toll that AMR will ultimately be responsible for, we are currently witnessing a worrying development, where more and more pathogens develop resistance to drugs of last resort that leave us with few if any treatment options, and threaten the safe delivery of healthcare around the world.

One thing to keep in mind here is that we do not rely on antibiotics for the treatment of acute infections alone. It has only been with the help of antibiotic prophylaxis that we have managed to reduce the rates of wound infections to levels, where complicated surgical procedures are safe for the patient. Losing effective antibiotics therefore means that we will lose one of the pillars that modern healthcare is built on. As a result, antibiotic resistance concerns all of us – and we should all be concerned about it.

While there is indeed great cause for concern, the political developments over the past year have been encouraging for those of us who are working in the field of AMR. Just last month the United Nation placed the issue front and center at its General Assembly in New York and vowed to bring the international community together to address what WHO Secretary Margaret Chan has called “an apocalyptic scenario”. As the discussions at the UN General Assembly made all too clear, there are no easy answers to the question how AMR can best be addressed at the international level. However, one of the aspects that is both maddening for those of us who have been working in this field for a long time, yet encouraging for the political process is that there is a general consensus about the areas in which we must act, if we want to reduce the effect of AMR in the future.

The key areas for intervention, which have been identified repeatedly and with great consistency are those that are listed in the WHO’s Global Action Plan on AMR, the US Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria, the UK’s AMR Review, or indeed our own German strategy DART 2020. They include:

1. Improving awareness and understanding of AMR
2. Strengthening the knowledge base through surveillance
3. Reducing the burden of AMR through effective sanitation, hygiene and infection prevention
4. Optimizing the use of antibiotics in human and animal health through antibiotic stewardship
5. Developing new drugs and diagnostic technologies

At an event I attended last week, I participated in a panel discussion with a group of medical students from around the world. We talked about AMR, and the conversation quickly turned to the question why – if we all agree on what needs to be done - we haven’t fixed the problem yet.

In the many years I have been working on this issue, both in veterinary and human medicine, this is a question I have frequently encountered. And the answer I tend to give is as frustrating to many audiences as it is true. First of all, the proposed areas for intervention, which I just mentioned are incredibly difficult to get right. We will only be talking about antibiotic stewardship today, which in itself could be (and indeed often has been) the topic of week-long workshops for the world’s leading specialists in this field. But to coordinate efforts in all five areas not just at the local or regional, but also at the national and even international level is a tremendous challenge.

A second thing that I often find myself reminding people of is that in spite of all the recent political engagement in the area of AMR, we will never truly “fix” the problem. If we work very hard, we may have a chance at keeping up with the development of resistance, and in an ideal world, we may even be one step ahead. But AMR is here to stay. Microbes have existed long before us humans, and chances are that they will still be here after we are gone. Therefore, as much as we need new drugs in our arsenal to fight infectious diseases, we should always remember that technological fixes will likely be temporary. The story of antibiotics is as filled with triumphs as it is with subsequent setbacks. And for every new drug – without exception – we have seen the rapid emergence of bacterial resistance.

There is, therefore, no silver bullet that we can rely on – and this brings me to the importance of the subject of today’s event. As much as we need innovation in the field of AMR, for example new drugs and diagnostic tools, we also need to work on conservation. As long as a large share of antibiotics are used irrationally, innovation alone will not be enough to slow down or even reverse the emergence of more and more drug-resistant infections. This idea of conservation, and of rational antibiotic use is at the very heart of antibiotic stewardship.

So what exactly do we mean by antibiotic stewardship, and why is it relevant? Broadly speaking, the concept refers to the elimination of unnecessary or irrational antibiotic use. For the fight against AMR this is an important area of intervention, because the overuse of antibiotics has been identified as one of the key drivers of resistance. And it matters to health care delivery, not only because it drives resistance, but also because it can help to reduce health care costs, as an excellent recent report from PEW has highlighted.

The CDC has estimated that in the US, such unnecessary use account for around 30 percent of all prescriptions. A recent report from PEW calculates that this is equivalent to roughly 47 million unnecessary prescriptions per year. But this is by no means a problem that is exclusive to the United States. Indeed, figures for many other countries are comparable. And even countries with an excellent track record of reducing the use of antibiotics often find that there remains much to do. Norway, for example, aims to reduce total antibiotic prescribing by 30% until 2020 in order to eliminate the majority of unnecessary prescriptions. Comparable targets exist in other countries, and will be a helpful step towards the implementation of antibiotic stewardship, and a benchmark against which ongoing efforts can be measured.

It is important to note that antibiotic stewardship is not limited to the use of antibiotics in humans, but applies equally to the veterinary sector. As a veterinarian, I have often seen the excessive use of antibiotics in animals, and also witnessed the consequences in the form of quickly progressing antibiotic resistance and infections that are becoming increasingly difficult to treat. The fact that an estimated fifty percent of the global production of antibiotics are used in the veterinary sector make an inclusion of stakeholders from this field all the more important.

Clearly, the unnecessary use of antibiotics is an obvious problem to tackle, if we want to address AMR. Yet, in practice this is often more complicated than it may appear at first sight. There are a number of seemingly obvious interventions to promote antibiotic stewardship that often fail to produce the desired effect. A better education of patients and prescribers about the risks of AMR, for example, appears to be a logical first step. And while everyone would agree that this is an important issue, education campaigns appear to only have a limited effect on a reduction in unnecessary use of antibiotics.

One explanation for this is that overprescription is not simply the result of a lack of information, but rather the result of a complex interplay of factors between prescribers, patients and regulators. These will not just depend on disease dynamics, but also on the organization and financing of health care systems, staff-to-patient ratios, cultural factors, or patient expectations.

For some of these factors, there may be institutional or regulatory solutions. This could involve tighter regulations regarding who can prescribe antibiotics, or how such prescriptions are followed up. In some Dutch hospitals, for example, antibiotic prescribing is already conducted with the help of an interdisciplinary “A-Team”, which evaluates the clinical evidence and routinely follows up on prescriptions, to de-escalate the therapy wherever possible. And I am happy to say that Germany is currently following suit by developing a curriculum for antibiotic stewardship, which will be instrumental in establishing similar structures. The Robert Koch Institute acts as a scientific advisor in the process. Furthermore, Germany is investing around 400 million Euros into a program to increase the number of infectious disease and hygiene specialists in hospitals. Based on risk factors that take into account the size, medical specialties and patient base, each hospital will be assigned additional staff for infection prevention. These specialists will work locally to reduce nosocomial infections and improve antibiotic prescribing.

There are also ways of delaying the start of empiric treatment, especially in outpatient settings, through prescriptions that can only be collected a day or two later. Studies in the UK have shown that this measure can greatly reduce antibiotic use, without a significant impact on patient outcomes. However, whether or not such approaches are implementable will in large parts depend on the structure of a health care system and the limits placed on the availability of antibiotics, especially in the many countries where they are available over the counter and without a prescription.

Inevitably, this means that there is no one approach to stewardship that will fit in all contexts. However, while specific solutions may translate poorly to other settings, and overprescribing may be triggered by a larger number of factors, the underlying principles of work on stewardship clearly show us that there are methods of engaging the relevant stakeholders that are transferrable and apply to a broad range of settings.

The PEW Trust has published extensively on this issue over the past year, and provided excellent summaries of some of the preconditions for the establishment of successful stewardship campaigns. They include, for instance, the presence of a local champion to drive the stewardship program, the creation of an interdisciplinary team, including pharmacists, infection control specialists and nurses, and stable funding. Similarly, resources like the CDC’s “Get Smart” campaign provide stakeholders with information and resources to advocate for and create stewardship programs. In Germany, we have taken the approach to specifically target prescribers in clinical settings. To this end we have developed a comprehensive guideline in collaboration with all relevant medical associations, which outlines all relevant steps for establishing and running a clinical antibiotic stewardship program.

In addition to the creation of structures and resources for the implementation of stewardship programs, a lot of promising research has recently been conducted on how the field of behavioral science can be used to avoid the unnecessary use of antibiotics. What is particularly interesting about this work is that it does not start from the assumption that prescribers and consumers are fully rational decision-makers that will arrive at the right conclusion when presented with sufficient evidence. Rather, it is acknowledged that all of us may at times act irrationally, and interventions are designed accordingly, in order to “nudge” us in the right direction.

An example of this is the work of Dr. Linder, who is in the audience today and who will join us for a panel discussion later today. He and his colleagues have shown that prescribers respond well to peer-comparisons and regular feedback on how their own prescribing compares to that of colleagues. Similar studies exist for the UK, where physicians received a letter signed by the Chief Medical Officer Sally Davies, informing them of how they ranked as a prescriber in their area. The Robert Koch Institute is currently rolling out a similar feedback system, which reports back to more than 200 hospitals on how their antibiotic use compares to that of others. In the future, we are planning to also combine this with local resistance data, to make the effect of excessive prescribing more visible for stakeholders. These are examples of concrete projects that are highly cost-effective and can be used to unnecessary use of antibiotics.

It is important to note, however, that none of these interventions eliminate the overuse of antibiotics altogether. And it remains to be seen, how sustainable their effects will be. However, much like our general strategies to tackle AMR, the successful implementation of antibiotic stewardship programs will ultimately depend on a number of different interventions that work concurrently to achieve the desired effect. What this underlines is not just the importance of information sharing, to learn what interventions exist and have been tried, but also that we must continuously monitor and evaluate stewardship programs, to ensure that their effect is not lost over time. We must therefore view antibiotic stewardship as an evolving discipline that adjusts to the problem and its audiences over time. This, I believe is the prerequisite for any successful stewardship strategy.

Another aspect of stewardship that matters greatly is to be clear about one’s goals and their implications. Over time, this may also mean that we have to face uncomfortable questions, about what it means to be a good steward. For example, does good stewardship only aim to eliminate prescribing that is entirely unnecessary, such as the use of antibiotics against a viral cold, or does stewardship also include the elimination of minimally effective treatments? When and how should antibiotics be available in the veterinary sector, and which drugs or drug classes should be entirely reserved for human use? Do we have to set targets for the reduction of antibiotic use, and if so what risk to the patient will be acceptable? Another way to pose these questions is to ask, what being a good steward ultimately commits us to do. These questions will likely not have simple or universally applicable answers or solutions. But we should revisit them from time to time to ensure that our interventions serve the goals we want to achieve.

Now, before we move on to our panel discussion, I wanted to share with you what I believe to be the crucial next steps in developing antibiotic stewardship further and successfully implementing it around the world.

As a scientist, I hope you will excuse that I start with the point that is the most important to me: we need better evidence. In order to see what exactly leads to a reduction in unnecessary antibiotic prescribing and use, we must collect and share our experiences, not just between countries but also between academic disciplines. Crucially, this will also help us to avoid duplication of research projects, and to incorporate lessons learned from other activities into new interventions. In Germany, we have set up the Network for Rational Antibiotic Use through Information and Communication (RAI) to this end, which will help to collect and process this evidence base, not just for human but also for veterinary medicine. And other resources, such as CDC’s excellent ‘Get Smart’ campaign are already available to give stakeholders access to existing programs and success stories, as well as an overview over key components of stewardship programs.

What I hope we can work towards is the support of similar research and advocacy programs in low and middle income countries. To date, most of the work on antibiotic stewardship focuses on high income countries with advanced health care systems. We should also work on creating a better evidence base for stewardship methods in resource-limited settings. Throughout its G7 presidency last year, Germany has focused on greater international collaboration in the area of AMR, and will continue to do so over the coming years. Likewise, the Global Health Security Agenda will offer an opportunity for member countries to support each other in twinning exercises and to share best practices, including in the field of antibiotic stewardship.

Similarly, we should expand the work on good stewardship principles and successful interventions in the veterinary sector, which often operates under very different conditions and includes entirely different stakeholders. It is encouraging to see that there is an increasing focus on ‘One Health’ in the field of antibiotic stewardship, but there remains potential for further strengthening of intersectoral collaboration.

And while I stressed earlier that there is no technological fix to AMR, antibiotic stewardship would nevertheless benefit greatly from improved diagnostics that allow for the rapid identification of pathogens to avoid empiric treatment with broad spectrum antibiotics. Initiatives such as the Longitude Prize and FIND (The Foundation for Innovative New Diagnostics) are important steps in this regard, but more work remains.

A final point I would like to mention is that globally, good antibiotic stewardship does not only mean that we have to restrict the use of antibiotics. While excessive use of antibiotics undoubtedly exists in many places, there remains a lack of access in other areas, where the antibiotic age, which we take for granted in the Western world, has never fully arrived. UNICEF, for example, estimates that in Africa, more children die from lack of access to antibiotics for easily treatable conditions like pneumonia than from drug-resistant infections.

Ladies and gentlemen, while the challenges we have to overcome may appear daunting at times, the political momentum to address AMR not just nationally but globally has never been greater, and antibiotic stewardship is one of the central pillars on which our strategies rest. I am hopeful that we will make use of this momentum and believe that this event is a great example of the kind of knowledge exchange we need to foster in the future.

In closing my remarks, I would like to leave you with an image that Prof. Otto Cars, a Swedish colleague of mine, often uses. His analogy to describe the role of antibiotic stewardship is the image of a leaking bucket. To develop new drugs without changing the way we use them is equivalent to adding water to the bucket, while to practice good stewardship is a way to stop the leaks. I like this analogy a lot, because it highlights the central role that stewardship must play in our fight against AMR. And I look forward to discussing with you, how we can come together to repair the bucket.

Thank you very much.

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