Antibiotic resistance: a healthcare emergency?

Thought LeadersIgnacio Martin-Loeches, Ph.DFJFICMI, Intensive Care Medicine ConsultantTrinity College, Dublin

An interview with Ignacio Martin-Loeches, PhD FJFICMI, conducted by April Cashin-Garbutt, MA (Cantab)

Antibiotic resistance has been described as ‘the healthcare emergency of our time’ – is this an accurate description?

Antibiotic resistance is happening in hospitals quite frequently. Probably the main place where resistant organisms and pathogens are acquired is in intensive care units (ICUs).

In hospitals, the main problem with resistance is that we have a huge consumption of antibiotics. This is something that has been happening for many years. I think we have been doing better over the last, say, decade, with the introduction of antibiotic stewardship programs.

“Antibiotic stewardship programs” is a marketing name for using the right antibiotics to treat the right patient in the right way. It is about is the need to administer and prescribe antibiotics to our patients wisely.

The main consumers of antibiotics are going to be the sickest patients in the hospital, especially those with comorbid conditions. Unfortunately, the patients that visit hospital nowadays are much more immunosuppressed; this is not just because of disease, since of course we have more oncology or cancer patients and so on visiting, but because we have more and more aging.

If we compare the medicine of today with twenty years ago when I started my clinical practice, it was not very common to have an 85-year old patient admitted to ICU – that was a very unusual case.

Nowadays, we have many patients that are quite old and age is no longer a reason to not accept a patient into ICU, because we have a longer life expectancy now. The second point is that we have many patients aged about 65 to 80 years who are still in very good shape, enjoying a good quality of life, working, having a good time and so on… so why not treat them?

We are going to provide intensive care medicine to them. We should do and I think it is very fair to do so, but the problem is that these patients are generally at a higher risk of becoming resistant to organisms.

This is a virtuous circle, because, as hosts, these patients are at risk of becoming resistant to organisms because they are weak. This means we have to use more drugs to treat them, but, at the same time, giving more drugs increases the antibiotic pressure that applies to the ecology of the whole ICU and in the hospital, we increase the resistance. We are paying the price sometimes for having these very advanced medicines nowadays.

How does antibiotic resistance arise?

The main problem behind antibiotic resistance is antibiotic pressure. Antibiotic pressure refers to the administration of antibiotics in the setting that you are looking after.

Hospitals that have less resistance are those that do better in terms of antibiotic prescription. They are not over-using antibiotics, first. Although sometimes a patient has a problem where it is very easy to say, "Oh, we have to not use antibiotics," there are other times when the patient in front of you is critically ill, at risk of death, and at a high risk of an infection.

In those cases, you cannot say, "Oh, I am not going to use an antibiotic, because I'm not going to increase the resistance in the others." You have to do it and this is fair enough, but at the same time, you have to use these antibiotics wisely.

However, sometimes we have to use antibiotics because the patients are becoming very sick. Sometimes we don't know what to do, but we have to deescalate, which is a key word in modern medicine for antibiotic prescriptions. We need do deescalate the treatment as soon as we can, which means to either stop the antibiotic or narrow the spectrum of the antibiotic.

On many occasions, we are using something very broad, when what we need to use is something narrow to target the specific infection and specific pathogen, without increasing the resistance to other pathogens. They can become very resistant, because they are going to be fed as a result of these antibiotics being given.

I think the first point is to improve diagnosis and control the administration of antibiotics. The second is to deescalate.

Another important issue is giving the antibiotics at the right dose. Often, with many of the prescriptions given to the public, the leaflet that comes with the antibiotics is based on many simulations given to healthy volunteers. Therefore, we often need to adjust the dose and the number of administrations we have to give to the critically ill patient.

The understanding of dosage has improved over recent years because the pharmacokinetics and pharmacodynamics in a very critical ill patient is something that is very important. If we do not give the right dose, we are either not going to treat the infection well or we are going to probably select, using lower doses, strains that are going to be very virulent.

These three points are important for treating the selection of resistant strains.

In your role as a consultant in Intensive Care Medicine, what impact of antibiotic resistance do you see on patients?

This is something that is very valuable. I am Spanish and have been working in different units in Spain, but I also work in a couple of units in Ireland. I see there is a huge variability in resistant organisms, depending on the country.

I could say that, more than the country, it depends on the hospital that you are working in. For me, one of the most important points when you are treating a critically ill patient in an ICU, is to have good communication with the microbiology department, because that department can provide a broad picture of what's going on in your hospital.

For instance, Pseudomonas aeruginosa is a microorganism found in many units in the world and, unfortunately, it is one of the most virulent pathogens that we have to face. Now, if you are comparing one hospital to another, sometimes hospitals have very low resistance to the Pseudomonas and they are fairly sensitive to all the antibiotics, while in other hospitals, you have what we call super-resistant bugs.

There are several classifications of these. When treating pathogens, they range from totally sensitive, meaning you can use any antibiotic, to multi-drug resistant, extensive-drug resistant, and pandrug-resistant.

With pandrug-resistant pathogens, no antibiotic whatsoever can be used to treat the infection. This is something that is happening more commonly than we think and there are many cases of it happening in the different countries that we see with these panresistant organisms. This is a big threat for us.

What changes have you seen over the last decade?

What I've seen is the difficulties faced by consultants in critical care, which is where we have the highest consumption in the hospitals and the most vulnerable hosts in the hospitals.

We have patients with conditions that are very critical in themselves and, at the same time, we have that superimposed by other comorbid conditions such as age, cancer and many others. My feeling is that over the last decade, we have become more conscious and more aware that as far as these factors are concerned, we need to all play together on the same beach.

I think that in the past, we were really aggressive and just thinking of the patient in front of us, without having a good understanding of the future implications for the other cohort of patients beside us.

There is an example that I use quite commonly with my registrars when we are prescribing antibiotics. I say that if we have a patient who has diabetes mellitus and you are using insulin to treat them, then that insulin is going to be a treatment for that patient and nobody else. The insulin is a drug that we use to decrease that patient’s blood sugar level.

By contrast, if you are prescribing an antibiotic to a single patient in the ICU, then that antibiotic is going to change the ecology of the whole unit. The more antibiotics we give, the more resistance we have.

Over the last decade, what I've seen is that in the intensive care community, we are more aware that we need to play a major role in decreasing antibiotic consumption. If we decrease or do more than that, by maybe more wisely prescribing short-term antibiotics at an adequate dosage whilst in good communication with other teams, then we are going to have less resistance. And I think that communication is key to that having happened over the last decade.

I think we also have more studies showing what the risk factors for resistance are. In the past, we were prescribing indiscriminately to patients, because we did not have research to use as a reference for critically ill patients.

Now, we know much more about what the determining risk factors are for patients and we understand more about dosage, pharmacokinetics and pharmacodynamics in critical care patients. Previously, many of the recommendations were concerning non-critically ill patients, but, thanks to ongoing research on pharmacokinetics and pharmacodynamics, we now have a better understanding.

I think that the rapid diagnostic tests are far from perfected, but we do have better tests to assess the sensitivity and the treatments that we do have for patients. In my opinion, these are the best tools for implementation of better care.

What are the main challenges to antibiotic research?

I think the main challenge is that we don't have public funding for adequate antibiotic prescriptions.

We have two problems, in different areas. One is a lack of development of new antibiotic classes. If you analyze the landscape of antibiotic discovery and research in new antibiotics, it has been very poor and very devastating.

Over the last twenty years, we have not developed many antibiotics and many of the ones that were developed did not reach clinical use. Having very few new antibiotics is the first thing that I consider very depressing.

Then, there is a lack of public funding, because many - about 80% - of the antibiotics we are using in intensive care medicine are the same across the world and are already generics. These antibiotics are not very important to industry, because they have been there for a long time, but these are the antibiotics that we are using all the time.

We are in the middle, because these antibiotics are not important to the industry on account of being old and, in terms of public funding, there are not new developments. I think that we are sometimes caught in the middle of trying to get new antibiotics and, with the old ones, thinking about how to give them wisely.

Also, different countries have put in place different strategies to get more funding and more research into antibiotic discovery, but the problem is that you need big parties, because while this may be happening in one country alone, that is not going to be enough. Thankfully, big agencies such as the European Union with the H2020 programs and the NIH in the U.S. are now understanding the problem much better.

I think they are putting in place more consortiums that are multi-disciplinary, so that the problem is seen from more than just one angle. They are getting clinicians, basic scientists and industries together and I think the success for research is based on this interaction.

For instance, clinical providers such as myself are not going to do anything if we do not have the industry helping us, because we need the industry to understand what we are looking for. I think these interactions between different counterparts in the story are what is going to make this successful.

What more can be done to prevent antibiotic resistance arising?

To prevent antibiotic resistance arising, I think we need to develop two things. The first is more rapid diagnostic tests. I think the diagnosis of infection is still very poorly and inadequately implicated.

For instance, nowadays, a patient with sepsis may have a positive result in perhaps 30 to 40% of cases. That means that we still have 60% of patients coming to the hospital with a severe infection, where we do not know the name of the disease pathogen. Also, when we do finally know, it's too late.

If I had to suggest something that would prevent antibiotic resistance, it would be knowing which resistance we were facing. We often don't know the name of the pathogen, because we cannot find it out and when do find it out, it's too late. I think the first prevention approach that is important is rapid diagnostic testing.

The second important prevention approach is having better antibiotics; new classes of antibiotics that are going to bypass the resistance that the pathogens are currently developing. We need to have more targeted therapies for treatment, as happens in other diseases.

For instance, many of the drugs that have been used in cancer treatment in the past were actually poisons: they were deleterious for many tissues, so whilst they cured cancer, they also caused huge side-effects.

Thankfully, now there is a lot of investment and there is a very personalized approach to cancer treatment. This, unfortunately, has not happened with antibiotic development. This is something that we don't have at the moment for infectious diseases in critical care. We don't have antibiotics that target just one single microorganism and, therefore, do not increase resistance to the others.

Sometimes, we need to have a rapid diagnostic test to know that something is MRSA, so that we can prescribe a treatment that is just for MRSA, without increasing the resistance to other pathogens, which would, of course, be deleterious.

A third important factor in preventing resistance, is that on many occasions, the treatment we give patients, decreases their immunity and changes the patients’ microbiota. Patients often have a very poor immune system.

Therefore, new things are needed such as improved analysis of what is happening with microbiota and fecal transplantation. Things like that are going to improve the way we approach developmental resistance in critically ill patients.

What do you think the future holds?

Nowadays, I do not feel as pessimistic as I did, say, ten years ago, when there was no movement and things were silent. Nowadays, things are happening and things are changing. If you saw the calls we receive, the number concerning antibiotic resistance is increasing. In terms of governmental investment, it is not just one government, but several different governments contributing together, because now the world is global.

We have patients that are traveling from one place to another. Unlike in the past, where one patient was born in a city and died in that city, we are now moving from one place to another, traveling quite a lot and we have patients that we have repatriated from other hospitals. All this means we are having more impact on the healthcare authorities in terms of developing newer strategies to decrease antibiotic resistance.

Also, we have better hospital programs. In the past, we worked in a very isolated way. The microbiologist did not talk to the intensive care physician and the intensive care physician did not talk to the pharmacologist. I think that interaction between different specialties, that multidisciplinary approach, will help us have a better future.

At the moment, there are many ongoing programs that involve good interaction with healthcare agencies, clinicians, universities and industry, with all of those working together to achieve the same goal.

This is something that has not happened previously, especially in Europe. If you compare America and Europe, I would say that, in America, it was more usual to have interaction with the industry, whereas this is something that did not happen very often in Europe.

There are several public agencies that are raising more awareness about antibiotics.

When we talk about antibiotics, I think education starts from the bottom. For instance, my wife is a GP and because of the number of problems you are facing when you are in a GP practice, you maybe do not follow the recommendations that are in place. Since patients are often working in a very fast world, they expect to be cured within 24 hours and if they are not cured within 24 hours, they are going to ask the GP for a new antibiotic.

This also happens in the hospital. I think that we need to follow a more “wait and see” approach and I think that the community needs to be involved in this because if we do not all work together, I think that we are not going to do great.

I think that we should all work together on this thing as a whole. I think following the recommendations made by the WHO and different national and international agencies based on the country, is something that is going to help.

I would also like to point out that over the last year, there have been many complaints made against vaccination. I think that this is a big, big mistake. I think that, as a result of these complaints, we are now discovering diseases that were not around before. This is important for healthcare, in that patients presenting with diseases that we did not have before will increase the treatment needed in hospitals and increase resistance.

I do agree that sometimes the public needs to be involved in decisions, but, at the same time, there sometimes needs to be a little bit more understanding of what healthcare professionals bring. I think this would help in future developments.

Where can readers find more information?

  • Gabor Zilahi et al. What’s new in multidrug-resistant pathogens in the ICU? Annals of Intensive Care2016 6:96 DOI: 10.1186/s13613-016-0199-4
  • Ignacio Martin-Loeches et al. Antibiotic therapy in critically ill patients: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee. Eur J Anaesthesiol 2017; 34:1-6 DOI: 10.1097/EJA.0000000000000595

About Ignacio Martin-Loeches, PhD FJFICMI

Ignacio Martin-Loeches, PhD, FJFICMI is a full time Consultant in Intensive Care Medicine and Senior Clinical Lecturer & Research Director of the Multidisciplinary Intensive Care Research Organization (MICRO) at Trinity College, Dublin.

Currently Vice-Chair of Intensive Care Medicine at St James’s University Hospital, Dublin. He has served as executive member for the European Diploma in Intensive Care (EDIC) and as Deputy for the Sepsis and Infection Section at the European Society of Intensive Care Medicine (ESICM).

He is the Chair of the Severe Sepsis and Septic Shock Working Group “4SWG” and executive member of the research-working group of the Surviving Sepsis Campaign (SSC).

He is the currently member of the Clinical Trials of Health Research Board in Ireland and the President of the Spanish Research Society of Ireland [(under the Embassy of Spain in Ireland and The Spanish Foundation for Science and Technology (FECYT)].

He is principal Investigator of European Regional Development Funds (ERDF) grant and the European Network for ICU-related respiratory infections (ENIRRIs) under the European Respiratory Society (ERS).

He has published several manuscripts in high impact factor journal and serves as section Editor at the Intensive Care Medicine (ICM) journal.

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