GIFTS-AMR conference on global research agenda: an impression for a new approach to antibiotic resistance

Antibiotics save thousands of lives worldwide every day. But antimicrobial resistance (AMR) is increasingly common, as antibiotics are used too often and unnecessarily. Despite efforts to reduce antibiotic use, annual global consumption is rising rapidly. The GIFTS-AMR research project advocates an additional approach: the use of drugs from traditional, complementary and integrative healthcare (TCIH) to prevent and treat acute, uncomplicated infectious diseases in humans and animals, thereby reducing antimicrobial resistance (AMR). There are several examples of TCIH approaches with a proven effect on infections in humans and/or various animal species. GIFTS-AMR drew up a research agenda with an international JPIAMR grant, identifying key priorities for international research. The agenda was presented at an online conference on 9 and 10 November, organized by participants of the GIFTS AMR project group like the Louis Bolk Institute and the University of Applied Sciences Leiden.

Antimicrobial resistance (AMR), insensitivity of pathogens to antibiotics, is a growing global problem. Worldwide, an estimated 5 million people die every year due to infections against which no effective antibiotic is available. In the coming decades, this number is likely to rise to 10 million. Increasingly, doctors are powerless against deadly infections. In low- and middle-income countries (LMIC), the problem is greatest. Wherever healthcare systems do not function optimally, antibiotics tend to be less well managed, increasing the risk of AMR. Already, 40-60% of human infections in countries like Indonesia, Brazil and Russia are caused by resistant microorganisms. But bacteria do not respect national borders. Eventually, they also end up in countries where AMR prevention has a high priority.

One Health

Some of the resistance arises from the use of antibiotics in animal husbandry and pets. Antibiotics and resistant micro-organisms end up in the food chain through animal manure and sometimes also through meat. It is therefore important to tackle the AMR problem in a One Health approach, involving humans, animals and the environment. An integral view of health and the use of TCIH medicines in principle fit well with this One Health approach.

International approach

GIFTS-AMR (Global Initiative for Traditional Solutions to Antimicrobial Resistance) is a research project funded by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), an international collaboration involving 29 countries worldwide. The growing GIFTS-AMR project group brings together research institutes and individuals from diverse backgrounds: researchers in human and/or animal infectious diseases, researchers in traditional, complementary and integrative medicine, policy makers, healthcare professionals and veterinarians. They share the conviction that a TCIH approach can contribute to better prevention and treatment of infections and the reduction of AMR.

State of the art: promising examples

The online conference of the GIFTS-AMR project group on 9 and 10 November 2023 opened with a discussion of the urgency of the AMR issue, both in Europe and worldwide. The most recent numbers from the World Health Organisation (WHO) show that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths[1]. In the EU/EEA, according to a 2022 ECDC report, more than 35.000 people die from antimicrobial-resistant infections each year, which is an increase from previous estimates[2]. Study results were presented showing that people carry and spread resistant bacteria for months after (a short-term) antibiotic treatment. This and other examples make clear that it is of utmost importance to use these valuable drugs only when there really is no other way.

The rest of the conference was devoted to approaches that can help prevent or even reduce AMR. A wide range of such approaches are already under development, both in healthcare and animal husbandry practice and in scientific research. To begin with, they often involve a different view of the problem, for example a shift in focus from disease and treatment to health promotion. This applies to both the prevention and the treatment of infectious diseases. From an integrated view of health, methods are being developed to better deal with infections, for example an app that helps patients, parents and practitioners deal with fever (see text box: Apps for better coping with fever). And then there is a wide range of traditional, complementary and integrative (TCIH) medicines. The effectiveness and safety of some TCIH remedies is so well established that they are part of German and English specialist guidelines for treating respiratory infections. There are also agents that have received a traditional use registration from the European Medicines Agency. The text box 'Promising TCIH drugs for the treatment of infections' names some examples.

For many other agents and approaches, the scientific evidence is not yet as advanced. The conference showed that a lot of research is already taking place worldwide, not only in the clinic but also in the laboratory. For example, it appears that some traditional herbal medicines strengthen defences against infections through specific changes in the immune system (immunomodulation).

Apps for better coping with fever

When a child develops a fever, it is often a reason for parents to call the doctor or give the child antipyretics. In most cases, however, fever is nothing more than a healthy body's reaction to a pathogen. In fact, fever is a useful reaction[3], supporting the immune system in dealing with pathogens. Sometimes, however, fever is a sign of a serious illness that needs to be treated (quickly) or the patient may suffer from complications. It is therefore important that parents and adult patients know what to look out for.

To better inform parents about fever, the FeverFriendTM team of Hungarian paediatrician and associate professor Dr Henrik Szőke developed an app. The phone app helps parents keep track of fever and provides science-based information to deal with the situation properly. According to Szőke's presentation at the online conference, the app reduces the number of needless visits to the doctor and the use of antibiotics. Szőke and his team at the University of Pecs collaborate, among others, with the university in Witten, Germany. The German university researchers also developed their own app, the FeverApp, which provides information and collects data on fever in children and adults. The FeverApp has versions in German, English, Russian, Arabic, Turkish, French, Farsi, Italian, Dutch and Polish.

Promising TCIH drugs to treat infections

Antibiotics are almost never needed for upper respiratory tract infections (colds, sore throats, irritable coughs). This is also stated in most guidelines. Similarly, uncomplicated lower urinary tract infections (cystitis) usually heal without antibiotics. But both types of infections do often involve discomfort, so patients understandably ask for treatment. Unfortunately, this often leads to the unnecessary prescription of antibiotics, especially in countries where patients and professionals are even less alert to the dangers of unnecessary antibiotic use.

The good news is that safe TCIH drugs are available that help reduce symptoms and promote recovery both in respiratory and in urinary infections. For instance, systematic reviews show that Pelargonium sidoides is beneficial in uncomplicated upper respiratory tract infections. A combination of ivy, primrose and thyme works against cough. It is also becoming increasingly clear how these herbs work. Pelargonium sidoides acts antivirally, indirectly antibacterially, and has immunomodulatory and expectorant properties. The ivy/ evening primrose/thyme combination combines the expectorant and airway relaxing effects of ivy with the antibacterial effects of thyme.

The effectivity of cranberries to prevent recurrent lower urinary tract infections in women has been demonstrated in many studies. Dog rose (rosa canina) also helps prevent urinary tract infections, according to a study in women who had undergone caesarean sections.

In animal husbandry, probiotics can help prevent infections and promote growth (antibiotics are still used for the latter purpose in many countries). In pigs with respiratory infections, for example, there is strong evidence that clove oil, Echinacea, thyme and marshmallow root can be effectively used. Many livestock farmers are open to such TCIH treatment of sick animals. Particularly in organic and biodynamic agriculture, they are already actually used, but in regular farming their application is still rare.

A pragmatic and focussed research agenda

The GIFTS-AMR project group developed a research agenda that reflects the current state of affairs. On the one hand, AMR is an urgent global problem, which could have catastrophic consequences in the coming decades, especially in low- and middle-income countries (LMIC). But while many citizens/patients and livestock farmers are open to using TCIH approaches and TCIH drugs to address this problem, many doctors and veterinarians are still reluctant. Scientific evidence of the effectiveness and safety of TCIH treatments against infections should change this.

In medicine, evidence acquired by the randomised controlled trial (RCT) is regarded as the most convincing form of scientific evidence. Setting up and conducting such studies is costly. The knowledge agenda therefore advocates a scoring system for prioritisation. The scoring should make it easier to decide which TCIH treatment should be considered first for comparative clinical trials. The knowledge agenda also identifies other ways of assessing the effectiveness and safety of TCIH treatments in infections, such as clinical data (real world evidence) and basic research. This should lead to a system by which recommendations can be made based on available scientific evidence.

The resistance of doctors, veterinarians and other professionals to TCIH treatment of infections deserves scientific attention in itself, according to the agenda. Understanding the factors that discourage professionals from using these treatments despite growing interest from the public can help implement proven effective TCIH interventions against infections and reduce antibiotic use. Conceptual differences between mainstream and TCIH approaches are an example of such factors. The agenda also advocates research on preferences, use, patient/pet owner/farmer satisfaction and acceptability of the TCIH approach in LMICs and western countries. And of course more high-quality research is needed on the (cost-)effectiveness and mechanisms of action of TCIH approaches in preventing and treating infectious diseases and reducing AMR.

Given the urgency of AMR worldwide and the opportunities in using TCIH approaches the GIFTS-AMR group presents, a logical next step is further coalition building. The research agenda calls for the integration of TCIH research into broader efforts to address AMR. Both at the European level and in the World Health Organisation, TCIH researchers and practitioners want to collaborate in tackling the urgent global problem of antimicrobial resistance.

[1] https://www.who.int//news-room/fact-sheets/detail/antimicrobial-resistance

[2] https://antibiotic.ecdc.europa.eu/en/european-antibiotic-awareness-day-eaad-2023

[3] https://academic.oup.com/emph/article/9/1/26/5998648