• Garance F. Upham

Jacques Acar's vision and critical thinking on AMR

Following the passing of Jacques Acar, here publish an interview of his vision and critical thinking about antibiotic resistance.

The Fight against Antibiotic-Resistant Bacteria: Let Us Not Hunt Rabbits!

By Garance Upham / September 2016.

Question: A pioneer in AMR, your experience goes back over 50 years, could you please tell us something about the history?

Jacques Acar: I am weary of ‘rabbit hunt’ like initiatives on AMR. I am of the generation of Thomas O'Brien, now 88, who was the first to put together a hospital program for surveillance of antibiotic resistance in 1970, and it is with him that we brought concern for AMR in the World Health Organization.

My master was Yves Chabert, then Chair for Bacteriology at the Pasteur Institute and the first national reference center for AMR in France. My first encounter with antibiotic resistance was in 1954 with a 21 years old German patient who had an endocarditis infection with Staphylococcus aureus. His infection was resistant to everything we had at the time, treated desperately with penicillin et streptomycin, he eventually died within a few days.

Question: Did you try bacteriophages on drug-resistant infections?

Jacques Acar: In 1960, faced with a purulent pleuritis with Pseudomonas aeruginosa, I recall that we did try a phage therapy with Jean-François Vieu, who was passionate on the use of phages at the Pasteur Institute, and would prepare lytic phages within a day or two, with always one preparation ahead of time. Phages worked well locally and very quickly, and when they did, the effect was spectacular, but it did not last. Since the administration could only be by local injection, in case of septicemia, it would not work.

Question: I participated in the European Medicine Agency meeting on phages last year, with people from Eliava Institute who still use them. Don’t you think we should use them on patients with untreatable MRSA wounds for example?

Jacques Acar: I'm in complete agreement with you. I think that the advantage of phages is that it has a very fast action.

Question: You told me once: "I find it wacky to call for fighting bacteria as if going to hunt rabbits!"

Jacques Acar: This 'rabbit hunt' joke was one of Chabert’s who mocked the way people would talk of 'The Bacteria', The Pathogenic Bacteria, as if an animal, against which we should arm ourselves to hunt, so as to prevent it from 'jumping' on to someone! Chabert used to remind us that bacteria are big communities in constant interaction and evolution in which human beings are immersed! Therefore, to start with: bacteria do not exist as individuals but as communities!

Question: You mean we can’t wage ‘war’ on bacteria?

Jacques Acar: Indeed! We can't run after and hunt down 'a bacteria'. This funny phrase about the Rabbit Hunt came back to my mind when I heard our Minister of Health say that we ought to go after all the travelers from India to have each of them having a feces culture for detecting bacteria harbouring NDM-1! I say: And then we do what? And further, would it be the same NDM? It is as if the bacteria was a bouncing animal to catch!

People imagine the pathogenic or drug-resistant bacteria as a sort of entity that we could track.

And the journalists write beautiful 'stories' on traveling and jumping bacteria: Klebsiella pneumoniae transporting KPC left New York, arrived in Israel, jumped on a few people and then packed and traveled again!

While hunting them down, we found them in various regions on earth, but it's always too late, they don't wait for us before multiplying or spreading, because, very simply, we are immersed in the microbial world!

People have failed to understand the notion of 'microbial community' and 'immersion'. interactions between microbes and the size of the communities are determinants for disease. Microbes are everywhere. People believe in pure air. Yet it is full of bacteria. The bacterial air transport system between continents has been carefully studied, one goes from Morocco to Canada crossing through Spain and France's Brittany. These airflow currents may carry a lot of the bacterial world within it. Well, and there are studies ongoing about the role of bacteria in cloud forming.

Question: The US and the European Union would like to establish a global management system to control AB, on the one hand, and, facing them, a number of emerging or low-income countries are arguing against (in the WHO Member States meetings I have attended). The later say that AMR is a rich country's problem since among the poor, there are a lot more deaths from lack of AB yearly than from drug-resistance. In your opinion?

Jacques Acar: I think that they are both right. It is good that you can pose the issues this way because I think that a very precise assessment is urgently required in each country: which antibiotics they have and which they don't have. We should organize ourselves in such a way as to have at our disposal, in each country, all the antibiotics which could be potentially useful. Let us not forget that France was among the last to have Avibactam in its different formulations! Hence, can you imagine what the situation is like in poor countries?

Remember the Belgian Dr. Lepage when he was facing an epidemic of salmonella among children, in a hospital in Rwanda, with resistance to amoxicillin, and sulfameth/trimethoprim! He did not have cefotaxim. Eventually, Roussel labs gave some and then people bought it and the epidemic stopped!

Question: So, in your opinion, the issue is to establish the data on the situation in terms of availability?

Jacques Acar: To me, it is fantastic that each country be able to establish its own assessment report on medicine availability! And in that, we meet the problem posed by developing countries: we have millions of deaths due to lack of access to medicines. And access to meds raises the need for countries to say: here we need this or that in that situation. There has to be people in charge, responsible for drug procurements, we, the countries in question, must have the possibility to order the antibiotics. And thus we go back to the assessment report which countries ought to do: which are the antibiotics locally available, are they supplied regularly? Where can they obtain them when needed? And so forth. Access is something that demands a good organization and new reasoning.

And it also demands to face the problem of counterfeit meds, and drug trafficking, see the report of the French Academy of medicines on this issue and the meeting of experts in Paris last April. Traffic in fake medicines is also a threat to our European countries.

Question: Aren’t there several questions there: if a medicine contains baby powder, it can’t be blamed for drug resistance, don’t we need to be specific?

Jacques Acar: Bad medicines come in many forms: nothing in the pill, another antibiotic than the one written on the label, the antibiotic mentioned on the label but at a very low dose!

There are countries where ciprofloxacin or the other fluoroquinolones will be commercialized honestly, but with doses which do not correspond to something useful.

Ciprofloxacin, for example, but at 20-milligram dose instead of 500 milligrams! That is also catastrophic and needs to come under surveillance. Selection through weak pressure can lead to resistance, especially as it selects for diversity.

Question: Do you think that the number of estimated deaths of patients in the EU/US due to drug resistance are trustworthy Are correct?

Jacques Acar: Estimates are to be taken with a grain of salt in my opinion. Estimates made with written down numbers are more viable than estimates into the future, but in general, they are not very precisely made. We know that people died, and when the death is attributed, at the last moment, to an infectious disease, it is not always clearly demonstrated.

Accepted figures are somewhat inflated because few persons have really gone through the trouble of a really precise proof on the cause of death.

In projecting figures for the future, there are assumptions: that the situation is as described, unchanging and that everything will remain the same for the next ten years.

Question: You often raise the crucial importance of appropriate treatment by the doctor? To me, this reminds me of my experience ten years as an expert volunteer with the WHO Patients for Patient Safety, seeking to decrease medical error.

Jacques Acar: I am very happy to have noticed recently that several authors wrote on the issue of proper prescribing of AB at the onset of treatment, like Timsit and Bassetti. A guideline is a very useful tool for thinking, it demands real monitoring of the patient with, as needed, a change in therapy. However they need to be constantly updated and be very detailed, and this is frequently not the case. When a guideline is one or two years behind times, beware! Guidelines can be the means to fall asleep! You follow them to the T, nothing can happen to you for malpractice in Court. If the guideline is not sufficiently detailed (nearly all the time, they never can be sufficiently detailed to fit exactly to the patient), or already behind times, beware! The guideline may be the opposite of personalized patient centered medicine! The problem is that we do need them, but they would have to be geographically precise, because resistance patterns will be widely different from one place to another, in fact the guideline needs to be established on the resistance pattern found in that particular region, hospital, where the health care is delivered and be always updated! Otherwise the treatment can be exactly according to guideline and the patient may die! It’s nice to know what’s going on in the world in general, for comparison, but to treat my patient correctly, I need information on what is the situation here, where I am. There should be no ‘blind’ automated treatment, just a probable diagnostic. The physician will try to treat before having received confirmation from the laboratory.

Question: What you demand scientific knowledge based on the laboratory testing, on diagnostic tools?

Jacques Acar: Absolutely, the doctor must have the laboratory on his side. That’s what I would like the lawmakers to understand. We have had to suffer from this nerve racking argument, for years, to the effect that we should reduce, cut down, the number of laboratory tests because doing these would be very COSTLY! If you have a patient with a urinary tract infection, just treat, it says, and if the infection doesn’t go away, then you can prescribe a lab test! NO! This is idiocy! We should do the laboratory test, while, in reality, it is often not done. On the contrary, the laboratory test is precious, and saves us costs and suffering. On this issue, I call upon economists to do the studies which demonstrate that to conduct lab tests properly and in due time costs much less to society than to postpone them. The samplings are often not done properly, people prefer to rely on symptoms rather than antibiograms. The limits in interpretation need to be re-evaluated, and cleaned up. Sometimes the fact that pathogens may overlap is not sufficiently taken into consideration. In African countries, a child with fever is immediately considered from suffering from malaria but a blood culture can uncover a bacterial sepsis case!

Question: So we come back to the issue of the need for laboratory testing, to identify the pathogen precisely and its drug susceptibility?

Jacques Acar: The issue of the laboratory is absolutely essential and must be examined through and through. I strongly believe that we cannot progress towards appropriate and reasonable use of antibiotics if we skip the diagnostic test capacities issue. There is a need to think through the realization of a good antibiogram, because it is not the same as measuring urea in the blood. It is a very difficult technique which is not always well carried out.

Question: Can you explain what you think is required for adequate measurement of bacterial response to AB?

Jacques Acar: There is a variation in the measure which we call the 'confidence interval'. I am critical of both EUCAST (The European Committee on Antimicrobial Susceptibility Testing) and the CLSI (Clinical and Laboratory Standards Institute) for never introducing the notion of confidence interval (CI) in what they report as Minimal Inhibitory Concentrations (MIC). The limiting figures: they don’t underline that the MIC has considerable CI !

When you measure how bacteria behave when in contact with antibiotics, you are in front of something highly variable. So the antibiograms are very difficult, and since it is difficult, it is poorly done, and it gets worse and worse, and when automated it has an ‘untouchable’ quality. It’s a 100 % value which is measured when doing a MIC measure, it is the antibiotic concentration that inhibits 100 % of the bacterial population. Yet in biology, it is very unusual because we know that the 100% values have considerable CI margins. Most biological measurements are done at 50%. We can take all this for negligible because antibiotics work so well- Chabbert used to say, him who was so extremely meticulous in the use of antibiograms and who taught me. When antibiotics' efficacy is questioned, a good diagnostic becomes essential.

Question: What of the environment in the emergence of resistance to AB, the role of wastewater, soil pollution, is that sufficiently researched?

Jacques Acar: Today, funding is offered for studies on the environment, but the calls only talk about antibiotics, which, in my opinion, is an error, because, since the technical aspects are the same as for other medicines, (or products, etc) we should also think of heavy metals, biocides, certain herbicides, some of the meds used against cancer (bleomycin, nitromycin), all this has anti-bacterial action! All this gives low selection pressure which favors biodiversity in resistance. If we are going to study the environment, we should have included anti-parasitic drugs, some of the antivirals used against HIV, or copper and zinc used in diarrhea, and in fact, we should have included ten other families of products which could also generate resistance and not just casting anathema on the antibiotic!

Question: The FDA just took out 19 biocides in hand soaps notably because of their potential role in AB resistance....! During our discussion, you also insisted on the need to investigate more the relationship between diverse diseases and pathologies? You made me think of TB and HIV, Helminthic infections and TB, TB and Helminth.

Jacques Acar: I am not an expert on TB, but in our times, HIV activates TB disease and infection with TB may facilitate HIV infection (according to the NIAID research back in 1996) and there are interactions with parasitic diseases to take into consideration. And of course, TB demands a long and difficult treatment where socio-economic considerations may jeopardize proper treatment (and be a cause of resistance). I think we need more clinical trials to learn how to better use the many antibiotics we still have, yet no one wants to pay for the antibiotics trials as old meds of generics are of no interest to industry. Public authorities should give it some thoughts: for example at what time should we initiate anti-staphylococcals among African children with measles? We know that in these children measle is often associated with pulmonary staph, and this leads to high mortality.

In my view, infectious diseases and their interactions are the key issues for the future! We are just beginning to know something about interactions of influenza virus, with bacteria like Pneumococci and Hemophilus. This should make us use antibiotics much more appropriately. I would be concerned about the tendency to overlook these interactions and tell docs outright not to use antibiotics. We will also have to face the issue of empirical inefficient treatments, especially when backed with outdated guidelines!

Question: On agriculture?

Jacques Acar: The pathogenic bacteria among animals in husbandry and humans are often not the same, nor are the modes of use in antibiotics. Just as a reminder: the travel path of food is long and contamination can occur any time along the way. WHO-AGISAR did a lot of work on the subject. The Codex Alimentarius has also a working group on AMR, and has worked on Risk Analysis applied to food security against resistant animal bacteria.

Question: An ecological approach, in conclusion?

Jacques Acar: Research on interactions among bacterial species and interactions among the cells which they use as support, would demand a lot more research. The word ‘ interaction’ is what is most important here: what needs to be delineated are ‘ecological units', functioning units, and not say outright, this species is good and that one is bad. A bacteria doesn’t exist in itself, it is not a highway robber. Let us have respect for ignorance! To try to explain everything is wrong. In praise of uncertainty, I say.

The above are only excerpts of a long telephone interview which Pr Jacques Acar kindly agreed to grant us.

Initially published in the newsletter AMR-Times, September 2016


In 1981, for the 30th anniversary of the discovery of antibiotics, Pr Yves Chabert did a video (INA.fr) which can be seen at https://enseignants.lumni.fr/fiche-media/00000000657/les-antibiotiques-ont-30-ans.html (en français – French only)