Europe Addresses Antibiotic Resistance

In November 2008, the first-ever European Antibiotic Awareness Day took place across Europe.¹ Its success has led to plans for this to become a regular fixture, with the third European Antibiotic Awareness Day held in November 2010. Although there have been previous efforts to tackle the problem of antibiotic resistance in Europe, the organisers behind the first European Antibiotic Awareness Day believed that improvements need to be made in sharing information and best practice.¹

The ongoing campaign has been promoted by the European Centre for Disease Prevention and Control (ECDC), an EU agency whose goal is to strengthen Europe's defences against infectious diseases. The campaign is also backed by the World Health Organisation (WHO), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Standing Committee of European Doctors (CPME), as well as a number of European healthcare professionals.¹

This broad, international participation has enabled the organisers to run a series of events held in different European member states during European Antibiotic Awareness Day. In 2008, for example, the inaugural campaign started with a scientific briefing and press conference at the European Parliament in Strasbourg (France), followed by national press conferences rolled out in EU countries ranging from Estonia to Greece. In a number of these countries, the Ministers of Health took part in the briefing sessions. As part of the campaign, leaflets and factsheets prepared in conjunction with local prescribers were distributed and a multilingual website was also launched.

The European Federation of Pharmaceutical Industry Associations (EFPIA) has welcomed the European Antibiotic Awareness Day initiative, but has also used the occasion to remind governments that the current drugs available are thanks to the historic efforts of the pharmaceutical sector.² It hopes that greater awareness of the issues surrounding antibiotic resistance will translate into support for the industry to produce next generation antibiotics. Given the high investment needed and the time lag to product launch in the existing regulatory and economic environment, however, it has been lobbying the European Commission to provide specific incentives to enable it to fast track its efforts. These moves appear to have had some impact; in 2009, Sweden used its Presidency of the EU to promote more open discussion of the industry's concerns on the matter.³

Tackling complacency

What has alarmed European governments, regulators and industry is that despite a growing availability of public information regarding antibiotic resistance, there continues to be a surprising level of misinformation and complacency around Europe.

In 2009, a pan-European survey was conducted on behalf of the European Commission to assess antibiotic awareness across the region.⁴ A total of 26761 facetoface interviews were carried out across 27 EU member states between November and December 2009. The timing of the interviews was designed to reflect the periods before and after European Antibiotic Awareness Day. The initial intention was to evaluate progress in public awareness and behaviour following a similar, although briefer survey, in 2002.⁵ Overall, however, the 2009 survey revealed worrying gaps in people's understanding of the issues surrounding antibiotic resistance even among those indicating exposure to previous public awareness initiatives.

As in 2002, around 40% of respondents indicated that they had taken antibiotics over the previous year, with greater usage being found in southern European countries. However, in the 2009 results, it was found that onethird of European respondents had taken antibiotics for a viral infection such as a cold or the flu.⁴ A disappointing outcome was the fact that a large number of respondents stated that new information provided on antibiotics did not change their initial viewpoint.

The lack of knowledge retention following public campaigns on antibiotic awareness is also problematic. A recent paper in the Journal of Antimicrobial Chemotherapy examined the effect of the 2008 English public antibiotic campaigns.⁶ Among respondents in England, there was only a small increase in recollection of campaign posters. In light of these results, the authors called for better auditing of the effectiveness of public campaigns and for better planning of such initiatives. They recommended targeting patients in physician waiting rooms and involving physicians themselves to relay the information.

Despite such disappointing outcomes, some national awareness campaigns have been reported as successes. In Belgium, a series of national public campaigns have been running since 2000, primarily over winter periods, and the initiatives have been given a high profile.⁷ The campaign was in two parts; one aimed at providing information to the public on the main issues (e.g. booklets and TV campaigns) and another providing specific clinical recommendations to healthcare professionals. The 2002 public campaign pieces had titles such as "Use antibiotics less frequently, but better", "Save antibiotics, they may save your life", and "Talk to your doctor, talk to your pharmacist". In 2004 it became more specific with one campaign piece entitled "Antibiotics are ineffective for common cold, acute bronchitis and flu". For healthcare professionals, the Belgian Antibiotic Policy Coordination Committee (BAPCC) produced evidence-based guidelines using scientific methodology for the appropriate use of antibiotics in particular conditions, such as sore throat and acute cystitis in women. All general practitioners received copies. Each year a consortium, including scientific colleges for general practitioners and the Federal Knowledge Centre for Healthcare, examined antibiotic prescribing data and provided feedback to GPs on their conclusions. All these primary care physicians were also invited to discuss these feedback reports with their peers in specially convened sessions.

Outpatient use of antibiotics, expressed in the number of reimbursed packages per 1000 inhabitants per day, dropped by a third between the 1997–1998 and the 2006–2007 winter seasons in Belgium. Apart from antibiotic usage, some benefits could also be shown in terms of actual resistance levels. This was most apparent when examining the proportion of nonsusceptible isolates of Streptococcus pneumoniae. For example, between 2000 and 2008, penicillin resistance decreased from 18% to 10% and macrolide resistance from 36% to 25%.⁷

The positive outcome in Belgium was followed by similar measures in France in 2001 through a campaign designed to counteract the idea that antibiotics should be used for viral infections.⁸ The campaign used the slogan "Antibiotics Are Not Automatic". As well as distributing information to the public, the authorities promoted better testing measures and guidelines directly to physicians through a process known as "academic detailing". When the two winters before the campaign were compared with five winters following the campaign, a dramatic effect was noted. A decline by 26.5% in the number of antibiotic prescriptions was achieved, which was more than the desired 25% target and the drop was seen in all French regions and age groups.

Such positive results appear to show that an effective and ongoing public campaign can have a real impact, but it still raises important questions about how such campaigns should be organised. From the Belgian and French experiences, a multi-faceted approach that focuses on both public and professional awareness has been recommended.^7,8 However, given different medical practices across the EU, as well as patient attitudes and behaviour, it would be presumptuous to assume that a campaign that has been successful in one country can automatically achieve success elsewhere. This is why European Antibiotic Awareness Day initiative has the potential to break new ground, as it takes into account the variations across the EU.

R&D hurdles

Raising awareness of antibiotic resistance is aimed at preserving the effectiveness of the currently available agents, but there is an urgent need to develop a new generation of antibiotics for the future. While some of the major pharmaceutical companies, such as Pfizer, GlaxoSmithKline and Merck, have maintained some interest in antibiotic R&D, most innovative research in this field is now being carried out by smaller companies.⁹

During the mid- to late-1990s, many large pharmaceutical companies reduced or abandoned antibiotic R&D programmes because the market was considered too crowded and financially unrewarding.⁹ The experience of Lilly, who developed daptomycin, convinced some companies that their efforts would be better spent in other areas.⁹ Daptomycin proved to have antibacterial activity, but was not considered particularly potent compared with existing agents on the market. In addition, it was found to have a narrow therapeutic window. During trials to examine higher doses, some volunteers developed muscle damage. Since Lilly already marketed vancomycin, an immensely popular broad-spectrum antibiotic, there was limited interest in funding another risky antibiotic R&D project. Even if successful, a new antibiotic might have ended up eroding the market for vancomycin.⁹ As a result of commercial nervousness, Lilly shifted its emphasis to other therapeutic areas considered more financially secure.

At the end of 2009, the Swedish government commissioned a study by the European Observatory on Health Systems and Policies to look at ways to provide new R&D incentives to pharmaceutical companies to carry out antibiotic research.³ As well as confirming that antibiotic R&D was considered a financially unattractive field for companies, it revealed underlying problems that would hamper any attempts to set up new research programmes.

According to the study, apart from commercial factors, antibiotic research in the pharmaceutical industry began to tail off partly due to a feeling that bacterial infectious diseases had been "conquered." As a result, many scientists chose to pursue research in other areas, believing them to be medically under-served. Over time, this shift in emphasis left a lack of industry personnel with the scientific experience to maintain the focus on antibiotic research.³ A number of well-funded training programmes have been initiated to give European scientists the necessary training to pursue antibiotic research, but trainees will still lack hands-on experience in dealing with infectious bacterial diseases. The European Observatory on Health Systems and Policies report concluded that as well as recruiting new scientists, efforts must be made to leverage the experience of older scientists. This may even necessitate asking retired scientists to mentor the next generation of antibiotic researchers. Only then will the pharmaceutical industry have the necessary pool of scientific talent to draw upon for new antibiotic R&D projects.

The report authors supported the idea that tax incentives could stimulate new industry antibiotic research.³ They recommended incentives to be focused on the earlier stages of R&D, as they felt that any measures linked to marketing or sales would weaken efforts to preserve current antibiotics on the market. As an example, it cited the policy approach of the French government in 2008, which was designed to make the country a more attractive environment for pharmaceutical R&D. The French Finance Act featured a reduced rate of corporation tax, but also provided preferential tax measures for various activities involved in the R&D process. For example, outsourced activities, expenses related to compliance with regulatory standards and social costs for employees with the necessary R&D expertise all had the potential to qualify for tax relief.

The study also identified a lack of information over how much new antibiotic research programmes might cost, which therefore complicates efforts to develop government policies for financial incentives. Generally, clinical trials for antibiotics are considered less complex than in other therapeutic areas, as the therapeutic endpoint is clear i.e., patient recovery from infection.³ This would suggest that R&D costs for antibiotic trials are less than say, for example, an oncology programme. Future trials, however, might involve additional costs as they might need to include a significant number of subjects with resistant pathogens.³ Since industry critics believe that pharmaceutical companies already generate excessive profits, financial incentives to kickstart antibiotic research might be publicised in the media as being unnecessary. However, the conclusions regarding the financing of antibiotic R&D programmes are based on historical data.

In summary

Antibiotic resistance remains a very serious threat due to the limitations of current agents and poor public knowledge about bacterial infections. The European Antibiotic Awareness Day campaign represents a continuing effort to combat these problems across the region, but measures are also needed to boost new pharmaceutical industry R&D efforts. Although the 2009 European Observatory on Health Systems and Policies report was a welcome step forward in summarising thinking of how to stimulate new industry research, it has not yet prompted governments to implement specific incentives. In 2009, a survey among European intensive care physicians found that 53% had treated at least one patient infected with a bacterium totally or almost totally resistant to available antibiotics during the previous 6 months.¹⁰ Worrying developments such as these are a warning that governments must bring a sense of urgency to incentivising new antibiotic R&D efforts.

References

1. About European Antibiotic Awareness Day (2008). antibiotic2008.ecdc.europa.eu

2. The overuse of antibiotics — Eurobarometer statistics. efpia.blogspot.com

3. E. Mossialos, et al., Policies and incentives for promoting innovation in antibiotic research (2010). www.euro.who.int

4. Antimicrobial Resistance, Eurobarometer 72.5 (2009). ec.europa.eu

5. Les Antibiotiques, Eurobarometer Special (2003). ec.europa.eu

6. C.A.M. McNulty, J. Antimicrob. Chemo., 65,1526-1533 (2010).

7. S. Coenen, et al., Acta Clinica Belgica, 63-5 (2008).

8. B. Huttner. Antibiotics Are Not Automatic Anymore — The French National Campaign To Cut Antibiotic Overuse. PLoS Medicine6(6) (2009). www.plosmedicine.org

9. L. Jarvis, An Uphill Battle (2008). pubs.acs.org/cen/

10. A. Lepape, Eurosurveillance, 14(45), 12 (2009). www.eurosurveillance.org