Over the past years the problem of antimicrobial resistance has received
increasing attention. At the level of the European Community (hereinafter
referred to as Community), a key element was the advice in 1999 of a committee
of independent scientists of the European Commission (hereinafter referred
to as Commission) recommending that the overall use of antimicrobials
should be reduced in a balanced way in human medicine, veterinary medicine,
animal production and plant protection (1). Following this recommendation,
a number of initiatives were taken. The European Union has, for example,
recently adopted a Directive to phase out the use of antibiotics as growth
promoters in farm animals (2). In the fields of plant protection and veterinary
medicine, several measures are also now in place and more legislative
acts are being prepared.
In 1999, the Council of the European Union (hereinafter referred to as
Council), drawing on recommendations of a European microbial threat conference
(3), adopted a Resolution: 'A strategy against the microbial threat' (4).
This resolution concludes that the problem cannot be contained by national
initiatives alone, but requires a common strategy at Community level.
As a follow up in June 2001, the Commission proposed a 'Community Strategy
against Antimicrobial Resistance' (5) (hereinafter referred to as Community
strategy), including a proposal for a Council Recommendation on the prudent
use of antimicrobial agents in human medicine (hereinafter referred to
as Council Recommendation), that was adopted a few months later by the
Council (6,7). The Council recommends that Member States implement national
strategies to contain antimicrobial resistance and charges the Commission
with a number of tasks to support Member States particularly through the
Community Network on the epidemiological surveillance and control of communicable
Community strategy against antimicrobial resistance
The Community strategy to combat antimicrobial resistance consists of
fifteen actions in four key areas: surveillance, prevention, research
and product development, and international co-operation (Table 1). Here,
the eleven points of action and the Council Recommendation are described
that are directly related to human medicine. Community related activities
are presented that received funding under the 1996-2002 Community action
programme on public health (hereinafter referred to as PHP) and through
the Fifth Framework Programme (hereinafter referred to as FP5) for Research
and Technological Development (1998-2002)(9).
Action 1 concerns the development of networks dedicated to surveillance.
The Council Recommendation calls on Member States to establish or strengthen
sustainable antimicrobial resistance and antimicrobial use surveillance
systems. Table 2 provides an overview of antimicrobial resistance related
projects funded under the PHP. The large European Antimicrobial Resistance
Surveillance System (EARSS) is a network of national surveillance systems
that currently comprises about 700 laboratories from 28 countries (10).
The main function of EARSS is to monitor variations in resistance of
indicator pathogens of major public health relevance and assist with
targeting interventions and assessing effectiveness of national intervention
programmes. Several other surveillance systems also monitor susceptibility
of pathogens. For instance, the 'Enter-net' network performs surveillance
of Salmonella and verotoxin-producing E. coli (VTEC) infections, including
the susceptibility to antimicrobials, whilst 'EuroTB' performs surveillance
of tuberculosis including (multi) drug resistant TB. Susceptibility
of meningococci, gonococci and syphilis is also being monitored.
Action 2 calls for improvement in the collection of data on consumption
of antimicrobial agents in all sectors. Such data exist in many Member
States but they are scattered, heterogeneous, and in many instances
not easily accessible. The Council Recommendation asks that Member States
co-operate with the European Commission to develop indicators to monitor
The Commission is funding, through the PHP, the European Surveillance
of Antimicrobial Consumption in humans (ESAC) project that started in
November 2001 with first results of the retrospective data collection
presented at the 13th ECCMID conference in Glasgow (11). Through this
network, some 30 countries deliver comprehensive national data on cost
and volume of antimicrobial consumption in ambulatory and hospital care.
Prospective and standardised data collection started in 2003 and indicators
to evaluate the appropriateness of antimicrobial use are being developed.
Also starting in 2003, the Antimicrobial Resistance in the Mediterranean
(ARMed) project, supported by FP5, aims to extend the implementation
of the defined methodologies of EARSS and ESAC into the Mediterranean
region, involving Malta, Cyprus, Turkey, Egypt, Tunisia, Morocco and
To guide intervention, it is critical to understand the relation between
antimicrobial resistance and use. A recent study using EARSS data showed
that in the EU, antimicrobial resistance of S. pneumoniae to penicillin
is correlated with use of beta-lactam antibiotics and macrolides at
country level (12). To further study and monitor the link between antimicrobial
resistance data and antimicrobial use, EARSS and ESAC are linking their
Action 3 of the Community strategy aims to increase the importance of
antimicrobial resistance information for the market authorisation process.
Regulators have expressed concerns that different indications, doses,
dose regimens (duration of treatment) and different pharmacodynamic
information exist for similar products already licensed in the EU. National
competent authorities in consultation with the European Agency for the
Evaluation of Medicinal products (EMEA) are currently considering the
issue of divergent product information and Member States are requested,
again by the Council Recommendation, to initiate activities to evaluate
and update and harmonise the summary of product characteristics (SPC)
where necessary. The EMEA has published a discussion paper on antimicrobial
resistance outlining its activities and points out the need to find
ways to promote new effective antibiotics (13). Criteria for market
authorisation of new antibacterial medicinal products are outlined in
three EU guideline documents (14, 15, 16).
Action 4 sets out to support educational campaigns to avoid overuse
and misuse of antimicrobial agents.
The Council Recommendation encourages Member States to promote education
and training of health professionals on the problem of antimicrobial
resistance. They should also promote training on hygiene and infection
control standards and immunisation programmes in order to reduce the
spread of microorganisms. The general public should be informed on the
importance of prudent antimicrobial use through raised awareness of
the problem of resistance, proper prescription, good patient adherence,
the value of hygiene, and the impact of vaccination.
The Commission is taking this forward in part by funding (under the
PHP) a television documentary on the battle against resistant bacteria
to be used as an educational tool to promote appropriate antimicrobial
use. Also, the FP5 supported European Resistance Intervention Study
(EURIS), is evaluating different approaches to reduce the prevalence
of resistant pneumococci among children in European day care centres.
These approaches include education of doctors, day care staff, parents
and children, optimised dosing, improved hygiene, notification of resistant
strains and isolation of carriers.
Finally, the Antibiotic Resistance Prevention And Control (ARPAC) project,
aims at identifying hospital policies and prescription patterns associated
with lower resistance rates to evaluate and harmonise strategies for
prevention and control.
Action 5 reinforces the principle that antibacterial substances should
be available in human and veterinary medicine by prescription only.
Antimicrobial agents for systemic use in human medicine are by law prescription-only
medicines in all Member States, but enforcement of this regulation varies.
The PHP funded project 'Self-medication with Antibiotics and Resistance
levels in Europe' (SAR) aims to quantify the consumption of antibiotics
sold over the counter (without prescription) and of leftover (prescribed)
antibiotics hoarded at home.
Action 6 concerns prevention of infections, and in particular immunisation.
The pneumococcal disease in Europe (PNC-Euro) project, funded by FP5,
focuses on the epidemiology of S. pneumoniae in a variety of European
countries prior to the introduction of new conjugate vaccines and aims
to design cost effective prevention strategies against pneumococcal
Containment of antimicrobial resistance is intrinsically linked to infection
control practices. Hospitals in Europe Link for Infection Control and
Surveillance (HELICS) is a Commission funded project (PHP) to monitor
hospital acquired infections, to develop protocols for databases on
surgical and intensive care unit infections, and to set up evidence
based infection control standards and recommendations.
The Council Recommendation appealed to the Member States to exercise
good practice in marketing antimicrobial agents. Member States should
implement preventive measures, ensuring proper implementation of hygiene
and infection control standards and encourage national immunisation
Actions 7 to 10 refer to preventive action in the fields of animal growth
promoters, food, and environment and, although indirectly very relevant
to public health, do not fall within the scope of this paper.
Research and product development
Actions related to antimicrobial resistance were initiated already under
the Fourth Framework Programme for Research and Technological Development
(1994 to1998), but efforts have been greatly reinforced during FP5.
Currently about 80 projects related to antimicrobial resistance are
funded at a total contribution of over € 100 million. This project
portfolio addresses anti-bacterial, anti-fungal, anti-viral and anti-protozoan
resistance through various approaches, covering research into basic
mechanisms of emergence and transmission of resistance, development
of new drugs and diagnostic tests and epidemiological and public health
research (a comprehensive overview of all these projects is available
Action 11 of the Community strategy promotes the development of new
antimicrobial agents. About one third of the antimicrobial resistance
project portfolio of FP5 is devoted to the discovery of new anti-infectives,
either through identification of novel molecular targets for the development
of new classes of antimicrobials or through exploitation of antibiotic
Action 12 of the Community strategy encourages the development of alternative
treatments and vaccines. Current FP5 research includes the development
of resistance inhibitors, such as inhibitors of bacterial conjugation
and bacterial adhesion. Lactic acid bacteria, already widely used as
probiotics for human consumption, are now subject to a rigorous biosafety
evaluation study. Vaccine development is a major priority in FP5 and
several research projects are currently on going with special emphasis
on tuberculosis, malaria, HIV/AIDS, and hepatitis C virus. Also influenza,
respiratory syncytial virus, shigellosis and Neisseria meningitidis
serogroup B are being addressed and efforts devoted to the development
of novel vaccine delivery systems and formula. In addition, a unique
effort has been launched in Europe to provide an infrastructure for
clinical trials of vaccines. This European and Developing Countries
Clinical Trials Partnership (EDCTP) has been set up by a joint collaborative
initiative among Member States and developing countries with the Commission
as supporting partner. The main goal is to support phase II and III
clinical trials of promising new clinical interventions against HIV/AIDS,
malaria and tuberculosis in, with and for developing countries.
Action 13 supports the development of rapid and reliable diagnostic
and susceptibility tests. Currently funded FP5 projects include the
development of sensors for multi-drug resistant strains of tuberculosis,
a DNA chip based diagnostic test for P. aeruginosa, nucleic acid based
amplification methods for the detection of respiratory pathogens in
community acquired pneumonia and a network for automated bacterial strain
Action 14 encourages the development of partnership at international
level, in particular via existing international organisations. The Commission
and the World Health Organisation (WHO) have signed a Memorandum of
Understanding reconfirming their common interest in health. Antimicrobial
resistance is among the agreed priorities and close cooperation with
WHO has been ensured for all antimicrobial resistance related networks.
The Commission is developing a programme with WHO on strengthening pharmaceutical
policies, including the rational use of drugs and particularly supporting
national programmes to contain antimicrobial resistance through the
expansion of projects that link surveillance data to rational prescribing
Action 15 attributes special attention to applicant and developing
countries. The participation of non-EU Member States is foreseen and
most candidate countries already participate in antimicrobial resistance
surveillance networks. The FP5 research portfolio on antimicrobial resistance
includes seven projects that are specifically focused on international
issues, covering broad geographical areas.
As has been presented here for human medicine, there is a wide range
of activities being undertaken at Community level and in Member States.
Community funded projects were initiated and through a legal provision
(7), recommendations for action were made. Whilst in other areas some
Community acts already existed (17, 18), for public health it was necessary
to add a separate legal provision in the form of a Council Recommendation.
Effective implementation requires several key features, including a
clear action plan, delegation of authority and power to act, resources
and sound mechanisms to assess the effectiveness of interventions and
thus allow feedback of results to influence future strategies. One of
the key conclusions of the Council Recommendation is that Member States
should put in place an 'intersectoral mechanism' for implementing relevant
measures and for effective coordination with other Member States and
the Commission. No specific recommendations are made as to the nature
of this mechanism, but one might assume that in this body local, regional
and national health authorities, the legislator, professionals of the
different disciplines concerned and consumers would be represented.
This national mechanism should coordinate reporting structures at local
and hospital level, prioritise the action needed, and charge the health
authorities responsible with taking action. The Commission has created
a working group of representatives of the different national intersectoral
mechanisms to assist in evaluating the implementation of the Council
Recommendation. Member States are to report to the Commission on the
implementation of the Council Recommendation within two years of its
adoption. The Commission intends to follow up on these reports to assess
whether the outlined Community strategy is successful or may need re-adjustments.
Disease surveillance networks currently face problems with comparing
susceptibility data because of differences in methodology and interpretation.
The Council recommends that the Member States build upon existing national
and international systems for collecting data and using, wherever possible,
internationally recognised classification systems and comparable methods.
It also asks the Commission to propose where appropriate, common methodology,
case definitions, and type of data to be collected and consequently
to support initiatives to standardise susceptibility testing in Europe
so that comparable results and interpretations are produced.
In 2002, a new programme of Community action in the field of public
health (2003-2008) was adopted (19). This programme provides an annual
public health work plan and a funding mechanism for projects addressing
priorities such as antimicrobial resistance.
Over recent years emphasis has been given to surveillance initiatives,
whereas the focus of future public health work plans may need to be
broadened. Activities that develop principles and guidelines for good
practice on the prudent use of antimicrobial agents are needed as well
as educational activities and intervention programmes to combat antimicrobial
The Sixth Framework Programme (FP6) for Research and Technological
Development (2002-2006) is supported by a set of new instruments designed
to ensure more effective research in Europe (20). These instruments
are 'Networks of Excellence' which aim to structure, integrate and coordinate
research resources and activities around a given topic and 'Integrated
Projects', which bring together expertise to address ambitious research
objectives. Research on antimicrobial resistance is one of the priority
areas also in FP6. The new instruments are a tool to channel microbial
and human genomic research towards applications such as new molecular
drug targets, alternative therapeutic and preventive strategies, new
diagnostic and susceptibility tests, epidemiological approaches and
improved knowledge of molecular mechanisms behind resistance. Furthermore,
measures to provide scientific support to antimicrobial resistance in
the context of public health (like intervention strategies and tools
for behavioural changes) are high on the FP6 agenda under policy oriented
research (21, 22).
In conclusion, in past years the problem of antimicrobial resistance
was addressed through an increasing number of individual measures. Through
the Community strategy, the Commission has outlined a more comprehensive
and pro-active approach to contain antimicrobial resistance, working
closely in partnership at international level, in particular with the
WHO. In addition to legislative measures the Commission considers antimicrobial
resistance as a key priority for its public health and research programmes.