From antibiotic dose fractionation to phage therapy: developments in the fight against antimicrobial resistance

Antimicrobial resistance (AMR) has been a major challenge for global human and animal health for several years. Therefore, the FAMHP is committed to fighting AMR with a number of concrete actions. The aim is to reduce and optimise the use of antimicrobial agents, particularly antibiotics, to prevent the development and spread of resistant germs.

In the fight against, a multisectoral approach is essential as humans, animals and the environment are inextricably linked. That is why the Belgian ‘One Health’ national action plan on the fight against antimicrobial resistance 2020-2024 has been set up. This plan, based on ten key lines of action, includes operational objectives and specific actions. Four objectives in the operational plan directly concern the AMR team of the Proper Use Division.

Arnaud Selvais – Sarah De Clercq – Karim Tamseddak

Reducing antibiotic use

One of the main objectives is to reduce antibiotic use in the ambulatory sector in Belgium. One of the options explored to achieve this is antibiotic dose fractionation. This means that patients receive the exact amount of antibiotics they were prescribed.

“Together with the National Institute for Health and Disability Insurance (NIHDI), the DG Inspection of the FAMHP, the Belgian Pharmaceutical Association (APB) and the Office of Co-operative Pharmacies in Belgium (OPHACO), we have drawn up an exhaustive list of the additional steps this would entail for pharmacists,” explains Arnaud Selvais.

For this measure to be effective, close cooperation between the various actors is essential. The NIHDI needs to allow unit pricing, and the FPS Public Health needs to oblige doctors to prescribe by substance name (international non-proprietary name, INN), by noting the name of the active substance, the dose and the precise duration of treatment in the prescription. The FAMHP will then be able to enforce the dispensing of the exact quantity of antibiotics through fractionation. Discussions are currently taking place with relevant actors to introduce this measure.

Improving the availability of antibiotics

A second measure taken by the FAMHP in the fight against AMR is improving the availability of antibiotics. The first step was to draw up a list of essential antimicrobials in the Belgian context. Karim Tamseddak explains: “We drew up the list based on the recommendations of the World Health Organization (WHO). This list was adapted to the Belgian situation through discussions with a panel of experts in the field who are involved in the Belgian Antibiotic Policy Coordination Committee (BAPCOC). In the course of these discussions, for each essential substance, we also defined the level of importance to work on in terms of improving accessibility. Based on this list, we prepared a state of play for the medicines linked to these essential active substances. We will continue our analysis using the data available, such as medicine life cycle and unavailability notifications, to assess the vulnerability of the supply chain for these medicines.”

Sarah De Clercq adds: “Our analysis of the supply chain is based on a study carried out by the European Health Emergency Preparedness and Response Authority (HERA). In this context, we’ve recently entered into a dialogue with DG HERA to discuss the possibilities of exploiting our respective information.” In parallel to this work, the FAMHP communicates to healthcare professionals when an antimicrobial innovation is introduced on the Belgian market.

Developing alternatives

A third measure in the fight against AMR is the development of alternatives to antibiotics, such as phage therapy. This method uses bacteriophage viruses (also known as phages) which target only bacteria. Therefore, phages cannot target human cells. This method is already being used to treat certain bacterial infections in Belgium. According to Arnaud: “Belgium is playing a pioneering role at European level in the use of phage therapy. The advantage of a bacteriophage is that it is highly specific, destroying only the targeted bacteria, which considerably limits the risk of adverse reactions. Unfortunately, phages are currently mainly used as a last resort, when antibiotic treatments have failed.”

The choice of this treatment lies with the doctor, who may prescribe phage therapy.

In such cases, if the patient meets strict eligibility criteria, the Queen Astrid Military Hospital (QAMH) provides applicants with phages specific to the bacteria responsible for the infection, if it has them available. Furthermore, all phages supplied by QAMH are analysed by Sciensano laboratories to ensure their quality. The pharmacist then makes a magistral preparation (a dilution). The aim of phage therapy is not to replace antibiotics, but to be a complementary therapeutic tool.

In veterinary medicine as well, phage therapy can be a valuable complement to antibiotics, which can reduce their use. Therefore, there is regular consultation between colleagues working on human and veterinary AMR.

Identifying suitable business models

“It’s often said that the antibiotics market is disrupted,” Sarah explains, “because there has been almost no innovation for decades. To reverse this trend, it is vital to introduce incentives to stimulate investment by the pharmaceutical industry.” To achieve this objective, we had to study existing business models and the various economic incentives available around the world.

“It’s important to be able to access expertise on these different models to enable decision-makers to assess their feasibility for Belgium,” says Karim.

Sarah concludes: “In the context of the above objectives, we are also working together with other European countries, in a ‘Joint Action’ EU-JAMRAI 2 (European Union Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections). In fact, in collaboration with Sciensano, our team organised a three-day kick-off workshop for a work stream that we are contributing to.”

From covenant to visible results: combating antibiotic resistance in animals

Antibiotic resistance not only affects humans; but also poses a serious threat to animal welfare. The Antimicrobial Resistance Entity of the DG PRE Authorisation is working closely with the industry in the fight against antibiotic resistance in animals. They too are basing their measures on the national action plan for AMR. “At the national level, as a follow-up to the first antibiotics covenant in 2016, a second antibiotic covenant was drawn up in 2021. This agreement was concluded between the Ministers of Agriculture and Public Health, represented by the FAMHP, the FASFC (Federal Agency for the Safety of the Food Chain) and the FPS Public Health, AMCRA (Antimicrobial Consumption and Resistance in Animals, the knowledge centre for antibiotic use and resistance in animals) and the stakeholders (agricultural organisations, veterinarian associations, the Order of Veterinarians,, Belgian Feed Association, managers of specifications and animal health associations),” explains Antita Adriaens.

This covenant contains various strategic and operational objectives as well as general, numerical targets, which are mainly about an overall reduction in antibiotic sales. “By 2022, antibiotic sales figures for animals were down 58.2 per cent from 2011,” notes Lies Van Nieuwenhove. “We are thus close to our goal of reducing sales by 65 % by the end of 2024, moving the total antibiotic use in animals in Belgium towards the median use in Europe. Cooperation between the industry and the government is very important in this regard. It’s certainly not always easy, but by working together we can take important steps forward.”

Guillaume De Cordes – Liesbeth Van Nieuwenhove – Inge Vandenbulcke – Cédric Maerckx

Objectives and reporting in veterinary medicine

“One of the goals we still need to work on is reducing the number of alarm users. These are livestock farms with systemically high antibiotic use. The target for 2024 is to reduce the number of alarm users to one per cent. There is still some work to be done, but thanks to the support of the food animal sectors, we are already making positive progress,” Antita explains. Therefore, in addition to antibiotic sales data reports, benchmarking reports are produced for livestock farmers and veterinarians of food-producing animals. The reports, which are prepared by AMCRA based on usage data for each animal category, are available to livestock farmers and veterinarians, with the intention of enabling them to consider together how to achieve sensible use of antibiotics on the farm. For example, based on this policy we can find out how many alarm users there are, what classes of antibiotics are being used and where best measures, such as mandatory coaching, are taken.

Since the implementation of Regulation 2019/6 on veterinary medicinal products in 2021, Member States are also required to report sales and use figures for antibiotics to the European Medicines Agency (EMA). With regard to sales, all marketing authorisation holders must enter the annual sales volume for each veterinary medicine into the European Union’s veterinary product database (known as the Union Product Database or UPD). Member States are themselves required to report the sales volume of certain antimicrobials to the EMA in a timely manner. “The advantage of collecting and reporting sales data at the Union level is that it helps to monitor the EU’s farm-to-fork strategy. This should achieve a 50 % reduction in antibiotic use in livestock and aquaculture within Europe by 2030,” says Lies.

In terms of use, reporting is happening gradually, starting in 2024 for food-producing pigs, cattle and poultry (all chickens and turkeys). From 2027, reporting must be extended to all food-producing species (fish, goats, ducks, sheep, rabbits, and all horses, including non-food-producing ones). By 2030 at the latest, pet animal data should also be reported. To make this possible, the VetAMRtool project was launched with funding from an EU grant. The aim is to create an automatic link with the register IN and the register OUT of the depot of the veterinarian and pharmacy. This will enable data on sales and use of antibiotics to be obtained while minimising any additional administrative burden on veterinarians.

Limiting the use of critical antibiotics

In the fight against AMR, both in humans and animals, it is also important to limit the use of critical antibiotics. Specifically within veterinary medicine, it is mandatory to perform an antibiogram or antibiotic sensitivity test before critical antibiotics can be administered to food-producing animals. Starting in September 2024, this requirement will be extended to companion animals and horses. This test must show which antibiotic is most appropriate for treating the bacteriological disease; a critical antibiotic should only be used if it is the best option or if it is the only appropriate antibiotic licensed in Belgium. This prevents bacteria from becoming resistant to antibiotics critical for humans and animals. Whenever possible, a non-critical antibiotic should be chosen. If the veterinarian decides to use a critical antibiotic, even if it is not substantiated by an antibiogram, he/she should always thoroughly justify it.

Antibiotic resistance knows no national boundaries and is an international problem. However, thanks to close cooperation with national and international bodies, the FAMHP continues to work tirelessly on systematic solutions and remains committed to the fight against antibiotic resistance. “All three of us are very passionate about this subject. I’m very proud of my team. Arnaud and Karim have put a lot of work into this issue, and all their research is very useful to us in our meetings with our partners,” says Sarah. Antita and Lies agree: “The issue of AMR is very complex. That is why it remains important to adequately consult and communicate with all stakeholders. Together, we have already been able to achieve some great results, and we want to continue that in the future.”

Our FAMHP experts

Sarah De Clercq, Arnaud Selvais and Karim Tamseddak form the Antimicrobial Resistance (AMR) team, part of the Information Entity of the Proper Use Division within DG POST authorisation. Sarah is head of the Information Entity and is Coordinator within the human medicines domain. Arnaud and Karim are file managers.

Antita Adriaens is head of the Antimicrobial Resistance Entity within the Medicines for Veterinary Use Division and works with Lies Van Nieuwenhove and her colleagues on rolling out projects relating to legislation, such as the new Regulation 2019/6 on veterinary medicinal products. They are also involved in implementing and coordinating actions on antibiotics included in the national action plan on AMR.