Jean Carlet, President, World Alliance against Antibiotic Resistance (Waaar) and Chair, National Task Force on Antibiotic Preservation, France; Anne-Claude Crémieux, Vice Président, National Antibiotic Plan Committee, Moh, France; Christian Brun-Buisson, Ministerial Delegate for AMR, Moh, Paris, France; Patrick Dehaumont, Director General for Food, Ministry of Agriculture, France; Benoit Schlemmer, Head, Antibiotic National Plan Committee, Moh, France and Benoit Vallet, General Director for Health, Moh, France
The French programme against antibiotic resistance has been intensified since 2000. A set of national plans have been developed, both for humans (three plans from 2001 to 2016), and in the veterinary setting from 2012 to 2017. Both plans were initially successful in decreasing antibiotic consumption, and antibiotic resistance for some microorganisms. The Minister for Health, Marisol Touraine, decided in 2015, to set up a special Task Force for Antibiotic Preservation because consumption was increasing again and because resistance from Gram-negative microorganisms was increasing sharply over the years. The Task Force proposed some important actions, in particular the creation of an interministerial committee and the nomination of a ministerial delegate for antibiotic resistance, the implementation of a five-year national research programme, special status for innovative antibiotics and a proposal that antibiotic resistance should be the main national cause for 2016. These proposals have been accepted by the Minister and some have already been implemented.
Resistance to antibiotics has sharply increased in the past 15 years and is a major concern worldwide (1, 2, 3, 4). An important contributor to this expansion is the extended-spectrum beta-lactamase (ESBL) pandemic in Enterobacteriaceae (5). In France, more than 10% of Escherichia coli isolates are resistant to third generation cephalosporins (3GC) (6), while in several countries this resistance rate can reach 50% to 80% (5), which results in the increasingly common use of carbapenems, a class of antibiotics which until recently were reserved only for severe and hospital-acquired infections. Not surprinsingly, carbapenem-resistant Enterobacteriaceae (CRE) have emerged over the past 10 years as a growing threat worldwide, rapidly expanding resistance rates to in excess of 50% in several countries (7). The treatment of infections due to those highly resistant bacteria requires complex combinations of old and toxic drugs like colistin; however, resistance to colistin has also recently emerged (8) and bacteria resistant to all available classes (i.e., pan-drug resistant or PDR) of antibiotics are now encountered more and more frequently, bringing back the fear of a “post-antibiotic era”.
There is ample evidence that resistance is strongly correlated with antibiotic consumption. In France, antibiotic consumption is high, both in hospitals and in the community, 30% higher than the mean consumption of European countries, and two to three times higher than those countries having low consumption and resistance rates, like The Netherlands, Sweden, Norway and Denmark (9). National programmes addressing antibiotic consumption and resistance have been designed and implemented in France since the early 2000s.
French plans to tackle antimicrobial resistance
France has implemented a comprehensive set of plans, involving all disciplines, to tackle antimicrobial resistance.
A) The three national plans for human medicine
Three human national plans were undertaken in 2001–2005, 2007–2010 and 2011–2016 (10) by the Ministry of Health, with the help of the French National Health Insurance system. Interventions were directed at the public, general practitioners (GPs) and hospitals, and included TV campaigns targeting unnecessary antibiotic prescription for winter viral respiratory tract infections (“antibiotics are not automatic”). Strep tests were also promoted to avoid unnecessary use of antibiotics for viral tonsillitis.
Other measures targeted antibiotic use in hospitals, such as the designation of a Local Antibiotic Committee in each hospital and a referral physician in charge of promoting local policy for prudent antimicrobial prescribing and to provide counselling to colleagues. These measures targeting hospital antibiotic use followed the implementation of the infection control programme emphasizing hand hygiene with alcoholic hand rubs to prevent transmission of multidrug-resistant (MDR) pathogens.
Mandatory public reporting of annual quality indicators of infection prevention were implemented in France in 2004; a specific indicator devoted to antibiotic policy became mandatory for every hospital and was made publicly available in 2006. In 2012, the French National Health Insurance system introduced a pay for performance process for general practitioners and specialists, with a quantitative indicator targeting a 5% reduction (42% to 37%) in the proportion of patients between 16 and 65 years treated with antibiotics (excluding patients with long-term illnesses).
The first results of these plans were quite impressive and actually exceeded expectations, with a 26.5% reduction in antibiotic prescriptions in ambulatory care over the first five years (between 2001 and 2005), especially for young children targeted by the campaigns, and a 50% decrease in penicillin-resistant Streptococcus pneumoniae rate. In parallel, antibiotic consumption was also reduced in French hospitals and there was a 50% decline in MRSA incidence in acute-care facilities over 15 years (11).
Unfortunately, the MRSA decline was soon followed by the rising incidence of other multidrug-resistant bacteria, especially third-generation cephalosporin-resistant Enterobacteriaceae. Furthermore, antibiotic consumption remained stable between 2007 and 2010, and increased slowly between 2010 and 2015.
In 2015, the Minister of Health appointed an expert group to make concrete proposals, specifically in the field of research and development of new antibiotics and new diagnostic tests.
B) The national programme for the prevention of healthcare-associated infections
The fifth and most recent programme for the prevention and control of healthcare-associated infections (HCAI) was launched in 2015 (“PROPIAS 2015”) (12). Encompassing acute care hospitals, long-term care and nursing home facilities, as well as ambulatory care, this programme is both a more focused continuum to the preceding ones, emphasizing patient safety, and a strong backup to the antibiotic plan. In fact, PROPIAS addresses only three strategic goals, one of which is entirely devoted to the prevention and control of antimicrobial resistance within the framework of HCAI.
This specific section on antimicrobial resistance encompasses four objectives:
- Ensure that patients and the public are fully involved in the fight against antibiotic resistance:
– through educational and awareness campaigns focusing on the prevention of cross-transmission via hand disinfection, and on the risks associated with over-consumption of antibiotics;
– by encouraging patients to participate in the annual “European Antibiotic Awareness Day.”
- Reinforce the observance of standard precautions for every patient, for every type of care, and at all sites of care:
– through promoting hand disinfection with alcoholic hand rub (AHR) products, whether in hospitals, long-term care facilities or the community. The promotion of hand hygiene has been operating in hospitals since 2005, when mandatory reporting of AHR product consumption was first implemented. Other publicly reported indicators on hand hygiene will be implemented shortly for the other two care sectors;
– through a number of specific measures and procedures targeting the prevention of transmission of MDR Enterobacteriaceae in all healthcare facilities.
- Control the diffusion of multi-resistant microorganisms, whether “classical” ones such as MRSA or ESBL producers, or highly resistant and emerging pathogens, such as vancomycin resistant enterococci or CRE, through specific screening and isolation procedures and, if needed, cohorting of patients.
- Decrease antibiotic consumption in hospitals through:
– use of rapid diagnostic tests for upper respiratory tract infections;
– vaccination programmes for patients and healthcare workers.
The PROPIAS programme on antibiotic resistance also suggests a number of research topics and includes quantitative indicators and targets for both hospitals, long-term care facilities and the community. One of these targets is to bring overall antibiotic consumption in France down to the mean European consumption level.
C) The national action plan to reduce antibiotic resistance in veterinary medicine
In line with the “One world, one health” concept, and the policy directions defined by the European Parliament and the European Commission as well as WHO, FAO and OIE, a national plan for the veterinary sector (ECOANTIBIO), was launched in 2012 under the auspices of the Ministry of Agriculture (13) (Fig. 1). As this plan is operated in close cooperation with the human plan at the Ministry of Health, the two ministries have organized a joint symposium since 2013 on the control of antimicrobial resistance close to European Antibiotic Awareness Day.
The ECOANTIBIO plan has two strategic objectives: firstly, to reduce the contribution to bacterial resistance of antibiotics used in veterinary medicine and its consequences on public health and secondly, to preserve the therapeutic options on a sustainable basis, given that the prospects for development of new antibiotics are limited in veterinary medicine.
The four key objectives of this plan include: 1) raising awareness of all stakeholders; 2) improving livestock farming practices (i.e, hygiene, farm building maintenance, animal health monitoring); 3) reinforcing partnerships between prescribers and animal owners and 4) promoting prevention and alternatives, such as vaccines. These objectives have 40 actions grouped into five headings. The plan also sets a target of reducing antibiotic use by 25% over five years, by promoting alternatives capable of protecting animal health while avoiding recourse to antibiotics.
1) Promoting good practice and raising stakeholders’ awareness of the risks associated with antibiotic resistance and the need to preserve the effectiveness of antibiotics
Adherence to good practice and asepsis, the design and up-keep of suitable buildings and veterinary healthcare facilities, application of biosafety and good sanitary monitoring are all effective ways of preventing and combating microbism and infection, the ultimate result of which is a reduction in the use of antibiotics. Dissemination of such good practice and increased awareness of all stakeholders (i.e., policy-makers, vets, farmers, scientists and risk assessors, pharmacists, the pharmaceutical industry and public opinion, including all animal owners) are priorities under the plan. In this regard, the veterinary plan has adopted and adapted the human health campaign motto and set up a large national communication campaign in 2014 directed to pet owners, based on the slogan “Antibiotics are not automatic for us either”. Another campaign is in progress to promote bovine vaccination, using the slogan “Fed, accommodated, vaccinated” (Fig. 2).
2) Promoting alternatives to reduce the use of antibiotics
Limitations on the use of antibiotics and promotion of good practice cannot be fully justified in the absence of the development of a varied range of alternatives that match the constraints of animal production and the care sectors. Experimental and research programmes are promoted to gain more knowledge of antimicrobial resistance dynamics and design new strategies for management of infections in animals.
3) Reinforcement of controls and reducing high- risk practices
Preservation of “antibiotics of critical importance” is an essential goal, both for human and animal health. The changes in European Union and national regulations recommended under the plan are intended to tighten the marketing conditions of such antibiotics, and the conditions for the provision of information and advertising targeting prescribers and right holders. Regulation of commercial practices and prescription rules, especially for antibiotics of critical importance for human health, were also enforced.
4) Consolidation of the system for monitoring antibiotic consumption and antibiotic resistance
European and national surveillance programmes are already providing data on the prevalence of resistance in zoonotic, pathogenic and commensal bacteria deriving from productive livestock. The French national agency for veterinary medical products (ANMV) has provided data on antibiotic use in animals since 1999. The aim is now to widen the scope of those programmes to include the links in the food supply chain judged to be relevant in line with EFSA recommendations.
5) Promotion of European approaches and international initiatives
The plan seems to be very effective, with a 12% decrease in antibiotic consumption over the first two years and some decrease in antibiotic resistance in certain sectors. This first ECOANTIBIO plan on veterinary medicine will end in 2016. An assessment will be made this year and a new five-year plan will be developed.
D) Others measures
Other initiatives were also undertaken between 2011 and 2015 which directly or indirectly contributed to the fight against antimicrobial resistance, such as the national programme for the prevention of infections in the medicosocial sector (2011–2013), the national programme for patient safety (2013–2017), the vaccine programme (2012–2017) and the re-organization of the regional surveillance and alert programme (2015).
Moving forward after 15 years of antimicrobial resistance plans
Despite some successes obtained over the period covered by the above plans, the continued increasing incidence of multidrug-resistant Enterobacteriaceae is worrying. To prevent further increases in resistance rates, more intensive action has to be taken, combining infection control measures, antibiotic stewardship and a sharp decrease in antibiotic consumption. Two major steps have been made in the past year.
A) Renewing the commitment to tackle antimicrobial resistance: The Task Force for Antibiotic Preservation (2015)
Deeply concerned by the antibiotic resistance problem and the paucity of new antibiotics, the Minister of Health, Marisol Touraine, implemented a task force in January 2015 whose mandate was to propose a limited number of innovative and original, but also pragmatic, recommendations to fight effectively against antibiotic resistance, decrease antibiotic consump tion by 25%, and facilitate research and innovation (14). The Task Force report was delivered to the Minister on 23 September 2015.
The five working group topics were: the impact of antibiotic resistance, antibiotic stewardship, communication and education issues, research and innovation, and antibiotic resistance and the environment.
Four major tools were proposed to secure the implementation of the task force recommendations: the creation of an inter-ministerial committee chaired by a delegate for antimicrobial resistance, in order to coordinate the various projects and actions of the several ministries and agencies involved, the development of a five-year national plan for research and innovation with appropriate resources, the designation of special status for innovative antibiotics or alternatives, allowing the implementation of a series of incentive measures, facilitating research and innovation for new compounds, and a proposal that antibiotic resistance is selected as the “national action theme” (grande cause nationale) for 2016.
The conclusions and propositions of the five working groups were the following:
- Impact of antibiotic resistance. A study (“Burden BMR”) performed by the National Institute for Public Health and Surveillance (InVS) estimated that 158,000 French people develop an infection due to multi-resistant microorganisms in France, out of whom 12,500 would die. The Minister asked that the number of deaths due to antibiotic resistance be reduced below 10,000 within three years.
- Antibiotic stewardship. Key proposals made by the group include:
- – Implementation of antibiotic stewardship teams in all hospitals and in every region in the community. The team’s role is to ensure good prescribing practices, including re-evaluation of antibiotic prescription on day two or three, and the appropriate duration of therapy; it also provides counselling to clinicians for the diagnostic and therapeutic management of patients with the most complex or severe cases;
- – Increasing the weight of antibiotic therapy in the “pay for performance” programme for general practitioners;
- – Identification and education of prescribers having the highest antibiotic consumption;
- – Updating, harmonizing and providing centralized access to guidelines;
- – Encouraging hospital management as well as healthcare practitioners, including veterinarians, to adhere to a roadmap for the proper usage of antibiotics;
- – Using a specific prescription order for antibiotics;
- – Providing patients with a non-prescription order explaining why antibiotics were not prescribed (available to GPs since October 2015);
- – Improving initial training of medical students, as well as continuous medical education programmes;
- – Elaborating quality indicators for antibiotic usage, in particular in long-term care facilities.
- National strategy favouring research on antibiotic resistance and the development of innovative products
- – Implementation of a national research programme on antibiotic resistance for a five-year period with appropriate and dedicated funding;
- – Improve the efficacy of R&D of innovative products and accelerate the numerous steps towards the marketing of the drugs;
- – Propose a new medicoeconomic model, in order to reduce the costs of R&D, extend the exclusivity of the drugs and revise the price fixing process.
- Propose indicators in order to measure and monitor antibiotic resistance, including its cost, in all sectors (humans, animals and the environment)
- – Implement medicoeconomic indicators of antibiotic resistance all over the health system in humans and animals;
- – Reinforce and better coordinate existing networks for the surveillance of the consumption of and resistance to antibiotics;
- – Set up research centres, coordinated by a national observatory of antibiotic resistance in the environment, in order to normalize the markers of resistance in the different life reservoirs.
- – Increase the awareness of healthcare providers and of the public of the impact of antibiotic resistance, by means of national and local actions.
B) The Interministerial Committee on Health: The “One Health” approach in motion
In 2014, the Prime Minister established the Interministerial Health Committee (IHC) (Comité Interministériel de Santé – CIS) with the aim of fostering dialogue between relevant ministries on health-related issues. The missions of the IHC are to: contribute to improving the population’s health and reduce inequalities; improve health literacy and health promotion in all public policies; and ensure that the coordination of public health policies is implemented at the regional level.
The IHC is chaired by the Prime Minister, or by a delegate of the Minister of Health, and is composed of representatives of the Ministries of Foreign Affairs, Health, Education, Research, Finance, Defence, Interior, Women’s Rights, Agriculture, Environment, Justice, Culture and Communication.
The IHC involves all the ministries of the French government and is the institutional structure for the essential principle: “Health in all policies”. The World Health Organization has recommended that by 2017, countries should have an antimicrobial resistance strategy based on the One Health approach. Whereas many countries have already created interministerial committees under the One Health approach, most of these committees involve the Ministry of Health and the Ministry of Agriculture. The IHC is based on a broader definition of the One Health concept since it involves not only the Ministries of Agriculture and Health but also Education, Research, Environment, Defence, Finance. In this sense it constitutes a good example of a comprehensive interministerial approach to tackling health-related issues.
Given the importance of addressing antimicrobial resistance at the national and international level, the Prime Minister decided that antimicrobial resistance would be the theme of the first meeting of the IHC.
This Committee will elaborate a roadmap on the fight against antimicrobial resistance by September 2016 that will address the issue from an interministerial viewpoint. To prepare this roadmap a permanent steering committee was established and several working groups created to support the implementation of this plan, which covers the following domains:
- surveillance and indicators;
- research and innovation;
- appropriate use, tools and guidelines;
- communication and awareness raising.
The work of this Permanent Steering Committee is coordinated by a Ministerial Delegate for Antimicrobial Resistance appointed on 2 February 2016.
Envisioning the future: Think global, act local
The rationale underpinning the national and international action on antimicrobial resistance has to be: Think global, act local”. Addressing antimicrobial resistance cannot be achieved through separate actions on animal, human health and the environment. France is convinced that a consistent, holistic approach to this issue through the appropriate definition of the challenges to be addressed at various levels is key to securing a concrete outcome. The various national, European and international initiatives that have emerged over the last decade have shown a great commitment to actively tackling this issue. France recognizes the outstanding quality of the outputs stemming from these initiatives and wishes to encourage greater cooperation and foster synergies among the various actors.
It is clear that WHO has the legitimacy to provide ambitious and strategic leadership to tackle antimicrobial resistance globally. However, one cannot assume that WHO will be able to achieve this objective alone. Political commitment at all levels is also key to securing concrete outcomes. The involvement of heads of state and governments (i.e., all ministries) to support this process has to operate in all countries. France has initiated this process and would be keen to share its experience in this regard.
Moreover, the full potential of antimicrobial resistance-related policies will be released when healthcare professionals, patients and healthcare providers understand that action at local and individual level has global consequences. Antimicrobial resistance is not solely a governmental or international issue, but must be addressed in daily practice by prescribers, in patients’ attitudes and public opinion as a whole.
As outlined in earlier, France has implemented several measures to tackle antimicrobial resistance and, as knowledge of the drivers of resistance increases, will further adapt its actions to the current challenges.
The four key words for the near future of the antibiotic resistance programme in France are:
- Prevention: To prevent the increase in resistance we must combine strong infection control programmes and antibiotic stewardship in the hospitals and the community. The evolution of the resistance of bacteria to antibiotics or treatments has to be closely monitored so as to enable evidence-based antimicrobial resistance policies. Data collection and sharing are therefore essential given that antimicrobial resistance knows no borders. Proper data collection methodologies and appropriate sharing of information will lead to better identification of risks and pave the way for efficient policies before the risk emerges into a bigger public health concern.
- Research: Supporting research is key to tackling antimicrobial resistance. The Task Force recommended establishing a five-year plan for research. It is essential that research projects are interconnected and funded according to a planned research strategy on antimicrobial resistance.
- Innovation: Innovation is also of paramount importance and needs an important budget, with public-private cooperation. There is a need to “take the special needs of antibiotics into account”. This is the reason why France advocates the creation of a dedicated regulatory framework for antibiotics leading to a specific status for antibiotics which would create roles for all the actors and allow incentives for both start-ups and pharmaceutical industries.
- Coordination: A strong political commitment and coordination of the various forces at a national, European and international level is essential to support the programmes and actions, in line with the recommendations of international bodies, such as OIE, FAO and, in particular WHO, which proposed to Member States a global action plan, adopted by the World Health Assembly in May
Each actor involved in tackling AMR – whether governments, research and public health institutes, healthcare professionals, patients or pharmaceutical industries – in their own field of expertise and interest in antimicrobial resistance, has to be part of the solution. Omitting some actors will result in a partial answer to the challenge raised by antimicrobial resistance. With full respect to each actor’s competence, France considers that coherent approach to antimicrobial resistance goes through the identification of the added value of each actor and their proper involvement in the solutions proposed to tackle antimicrobial resistance.
Professor Anne-Claude Crémieux, MD, PhD, is Professor of Infectious and Tropical Diseases at the Hôpital Raymond Poincaré APHP, University of Versailles. She has been National Physician Adviser to the Agricultural Social Insurance Mutual Benefit Fund (MSA) since 2013. She was also Vice President of “The national plan to keep antibiotics working” at the Ministry of Health from 2003 to 2006 and adviser to the French Minister of Health from 2003 to 2005. Previously, Professor Crémieux was Head, Anonymous HIV Test and STD Department, Bichat-Claude Bernard Hospital, Paris from 1995 to 2005.
Dr Christian Brun-Buisson is Professor of Medicine and Intensive Care at University Paris-Est Créteil, and Director of the Infection Control Unit at Henri Mondor University Hospital, Créteil, France. He chaired the steering committee for the French national programme for prevention and control of healthcare-associated infections at the Ministry of Health (2005–2015). Since February 2016, he has been appointed as the ministerial delegate for antimicrobial resistance at the Ministry of Health.
Patrick Dehaumont is Director General for Food in the French Ministry of Agriculture since 2012. He is in charge of plant health, animal health and welfare and food safety . From 2002 to 2010 he was Head of the French Agency for veterinary medicines.
Dr Benoît Schlemmer is currently Professor of Critical Care Medicine at University Paris-Diderot, France and Chief of the Department of Critical Care Medicine at Saint-Louis Hospital in Paris. He was an expert at the French Medicines Agency and at EMA in the field of evaluation of anti-infective drugs, and for 15 years the Chairman of the French advisory Group for Anti-infective Drugs. He was involved in several guidelines for the evaluation of antibiotics and recommendations for their use in current medical practice. He is the Chairman of the National Committee “Keep antibiotics working” at the French Ministry of Health since 2002 which promotes good antimicrobial practice and fights against antibiotic resistance in France.
Professor Benoit Vallet was appointed Director General of Health on October 23rd 2013, on the recommendation of Mrs Marisol Touraine,Minister for Social Affairs, Health and women’s rights. Before that, he was the Chair for the Anaesthesia and Intensive care Clinic in the University Hospital of Lille (Northern France), President of the Medical Executive Board and President the French Society of anaesthesia and intensive care. ProfessorVallet contributed to several international scientific groups and in particular was involved in European affairs as a member of the European Union of Medical Specialist (UEMS). The UEMS is a non governmental organisation representing medical specialists at the European level and advocating for the improvement of the quality of care through highest standard of training of medical specialist. He notably contributed to the elaboration of Common Training Framework in Intensive Care Medicine. Professor Vallet was also member of the COBATRICE initiative, an EU-funded project that elaborated a competence-based training for specialists in Intensive Care. He is now involved in the WHO governing bodies as vice-chair of the WHO for Europe Standing Committee and represents France within the WHO Executive Board since May 2015.
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The English translation of the Task Force on the Preservation of Antibiotics, chaired by Dr Carlet, is available at : http://esgap.escmid.org/?p=1288