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ANTIMICROBIAL RESISTANCE
An Integrative Research Perspective
Erik W. Baars
MD, MSc Epidemiology, PhD Senior researcher Healthcare, Louis Bolk Institute
Professor Anthroposophic Medicine, University of Applied Sciences Leiden
Four perspectives
• Worldwide problem: can CAM/IM (Complementary & Alternative Medicine/ Integrative Medicine) provide a contribution? (Value creation and delivery)
• CAM uses different concepts > CAM sees/looks different > CAM acts different. (Specific contribution)
• The contribution should be of good quality. (Evidence-based)
• An organization network of practice, research and civil society actors and a long-term program is necessary to demonstrate/ realize/ deliver the CAM contribution. (Organization)
Four perspectives
• Worldwide problem: can CAM/IM (Complementary & Alternative Medicine/ Integrative Medicine) provide a contribution? (Value creation and delivery)
• CAM uses different concepts > CAM sees/looks different > CAM acts different. (Specific contribution)
• The contribution should be of good quality. (Evidence-based)
• An organization network of practice, research and civil society actors and a long-term program is necessary to demonstrate/ realize/ deliver the CAM contribution. (Organization)
The problem
• Drug resistance: – Bacteria (antibiotics)
– Viruses (antiviral medicines)
– Parasites
– Fungi
– …
The problem
• Drug resistance: – Bacteria (antibiotics)
– Viruses (antiviral medicines)
– Parasites
– Fungi
– …
• Antibiotic: – Any class of organic molecule that inhibits or kills microbes by
specific interactions with bacterial targets, without any consideration of the source of the particular compound or class.
The problem • Multi-drug resistance:
– M. tuberculosis
– Acinetobacter baumannii
– Burkholderia cepacia
– Campylobacter jejuni
– Citrobacter freundii – Clostridium difficile
– Enterobacter spp.
– Enterococcus faecium
– Enterococcus faecalis
– Escherichia coli
– Haemophilus influenzae
– Klebsiella pneumoniae – Proteus mirabilis
– Pseudomonas aeruginosa
– Salmonella spp.
– Serratia spp.
– Staphylococcus aureus
– Staphylococcus epidermidis – Stenotrophomonas maltophilia
– Streptococcus pneumoniae
– …..
Source: Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance.
Microbiology and Molecular Biology Reviews, 74(3), 417-433.
Historical development
Source: Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance.
Microbiology and Molecular Biology Reviews, 74(3), 417-433.
Historical development
• “Erythromycin was an early example; introduced as an alternative to penicillin for the treatment of S. aureus in Boston City Hospital in the early 1950s, it was completely withdrawn after less than a year because 70% of all the S. aureus isolates were found to have become erythromycin resistant. The same was observed with chlortetracycline and chloramphenicol and, subsequently, with other antibiotics (55). It is clear that antibiotic resistance seems inevitable.” (p. 428)
Source: Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance.
Microbiology and Molecular Biology Reviews, 74(3), 417-433.
Mechanisms of resistance
• Mechanisms of resistance:
– Genetic
– Biochemical
– ..
• Examples: – The formation of microbial biofilms
Mechanisms of resistance
Source: Brown-Elliott, B. A., Nash, K. A., & Wallace, R. J. (2012). Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clinical microbiology reviews, 25(3), 545-582.
Mechanisms of resistance
Source: Wilson, D. N. (2014). Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology, 12(1), 35-48.
The problem • Humans can be infected in various ways with antibiotic-
resistant bacteria. The most common routes are: – The use of antibiotics.
– The transfer of drug-resistant bacteria between people, for example, in hospitals or nursing homes.
– Travelers can carry resistant bacteria from abroad.
– Animals can transmit resistant bacteria to humans. For example, farm animals, but also companion animals such as dogs and cats.
– Resistant bacteria can be transmitted to humans via the environment (soil, water, air, fertilizer, (swimming) water).
– Food contaminated with resistant bacteria can infect humans.
The burden
• In the USA yearly at least 2 million people are infected with resistant bacteria.
• An estimated 25.000 people infected with multidrug-resistant bacteria die each year in the EU.
• Infections caused by these multi-resistant bacteria in the EU lead to: – additional healthcare costs of at least EUR 1.5 billion per
year, and
– loss of productivity. Sources: EMEA, 2009; CDC, 2015
The burden
• “Drug-resistant infections already kill hundreds of
thousands a year globally, and by 2050 that figure could be more than 10 million. The economic cost will also be significant, with the world economy being hit by up to $100 trillion by 2050 if we do not take action.” Jim O’Neill, Vorsitzender von ‘Review on AMR’, United Kingdom.
Policy
• Global: – WHO
– G7
• EU:
• National: – Bundesrepublik Deutschland – Gesetzesinitiative zur
Antibiotikaresistenz Bundeskabinett Mai 2015
Policy
• Main strategies: – Infection prevention and control of resistant bacteria
– Monitoring of both infection prevention and control of resistant bacteria
– Research on antibiotic resistance and antibiotic use
– Appropriate use of antibiotics (e.g. not for viral infections)
– Less antibiotic use (e.g. delayed prescription and alternatives) – Development of new antibiotics*
*In practice, few new antibiotics have been developed. The costs for developing new antibiotics are that high that the pharmaceutical companies do not receive sufficient return on their investment.
Policy
Source: Wilson, D. N. (2014). Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology, 12(1), 35-48.
The problem: summary
• Drug-resistance
• Burden: increasing mortality and costs
• Current strategies: no change in prescription rates
• Search for innovative strategies aiming at: – Less antibiotics prescription & consumption – Appropriate use of antibiotics
– Alternatives for antibiotics
The problem: summary
• Drug-resistance
• Burden: increasing mortality and costs
• Current strategies: no change in prescription rates
• Search for innovative strategies aiming at : – Less antibiotics prescription & consumption – Appropriate use of antibiotics
– Alternatives for antibiotics
• Is there a contribution of CAM/IM?
The problem: summary
• Can CAM/IM provide innovative strategies aiming at :
– Less antibiotics prescription & consumption
– Appropriate use of antibiotics
– Alternatives for antibiotics
Four perspectives
• Worldwide problem: can CAM/IM (Complementary & Alternative Medicine/ Integrative Medicine) provide a contribution? (Value creation and delivery)
• CAM uses different concepts > CAM sees/looks different > CAM acts different. (Specific contribution)
• The contribution should be of good quality. (Evidence-based)
• An organization network of practice, research and civil society actors and a long-term program is necessary to demonstrate/ realize/ deliver the CAM contribution. (Organization)
The specific contribution of CAM/ IM
• What is next in the row?
32, 38, 44, 48, 56, 60, ‘Meadowlark’
The specific contribution of CAM/ IM
• What is next in the row?
32, 38, 44, 48, 56, 60, ‘Meadowlark’
The next station after 60th street
The specific contribution of CAM/ IM
• Interim conclusions: – We need concepts to perceive/ see and to act.
– Depending on the content of the concepts we perceive/ see different things and act differently/ find different solutions.
The specific contribution of CAM/ IM
Worldviews are frameworks of meaning and meaning-making that shape how individuals perceive
particular issues and their possible solutions.
They also tend to influence the willingness of individuals to participate in these worldview-related
solutions.
Hedlund-de Witt, A. (2012). Exploring worldviews and their relationships to sustainable lifestyles: Towards a new conceptual and methodological approach. Ecological Economics, 84, 74-83.
The specific contribution of CAM/ IM
Worldviews have five aspects that are interrelated and interdependent: (1) Ontology: a perspective on the nature of reality; (2) Epistemology: a perspective on how knowledge of reality can
become about; (3) Axiology: a perspective on what a good life is, in terms of morals and
quality of life, ethical and aesthetic values; (4) Anthropology: a perspective on who the human being is and what his
role and position in the universe is; and (5) Societal vision: a perspective on how society should be organized and
how societal problems should be addressed.
Hedlund-de Witt, A. (2012). Exploring worldviews and their relationships to sustainable lifestyles: Towards a new conceptual and methodological approach. Ecological Economics, 84, 74-83.
The specific contribution of CAM/ IM
• Whole Medical Systems (WMSs)– WMSs are complete systems of theory and practice that have evolved
independently from or parallel to conventional medicine.
– WMS practices often involve complex interventions, composed of parts that together make the whole intervention, in which the whole is more than the sum of the parts, and, in which the whole can generate the effect of the intervention.
– WMS examples:• Homeopathy• Traditional Chinese Medicine (TCM)• Ayurveda• Naturopathy• Anthroposophic Medicine (AM)
The specific contribution of CAM/ IM
• Concepts: – Basic supporting concepts:
• Health & disease:
– in general
– specific: infections
• Fighting disease vs. health promotion
– Prevention concepts:
• Elements, organization of the elements and working mechanisms/ principles of CAM/IM prevention
– Treatment of infections concepts:
• Elements, organization of the elements and working mechanisms/ principles of CAM/IM treatment
The specific contribution of CAM/ IM
• Prevention strategies concepts: – CAM promotes a lifestyle and treats patients (e.g., restricted
application of vaccinations, restricted use of antibiotics and antipyretics in infections, use of natural remedies and external applications) in a way, that is aiming at supporting and strengthening the self-healing or self-regulating ability of the human organism to cope with (infectious) diseases.
– As a result of this CAM approach: • it is hypothesized that the organism in general will become both
less vulnerable for infections (prevention) and more resourceful/ resilient in overcoming occurring infections (self-regulation).
• there is a restricted prescription of antibiotics.
The specific contribution of CAM/ IM
• Treatment strategies concepts: – CAM treatment of infections is characterized by the use of:
• natural medicinal products
• non-medicinal treatments (e.g., external embrocation, compresses, nutrition)
• complex, multimodal interventions
– CAM treatment is aiming at: • curative health promotion (to a large extent)
• bactericide or bacteriostatic effects
• targeting gut microbiota and related immune functions
– As a result there is a restricted prescription of antibiotics.
The specific contribution of CAM/ IM: summary • We use concepts to see and act.
• CAM/IM provides additional concepts (basic concepts, prevention treatment).
• These CAM/IM concepts theoretically result in: – Less antibiotics prescription & consumption:
• Indirectly: by strengthening the organism in general to become both less vulnerable for infections (prevention) and more resourceful/ resilient in overcoming occurring infections (self-regulation)
• Directly: by restricted prescription of antibiotics
– Appropriate use of antibiotics: • By providing alternatives ((non-)medicinal treatments) that answer the needs of
doctors to treat and the needs of patients to be treated and receive a prescription
– Alternatives for antibiotics aiming at: • Curative health promotion (to a large extent)
• Bactericide or bacteriostatic effects
• Targeting gut microbiota and related immune functions
Four perspectives
• Worldwide problem: can CAM/IM (Complementary & Alternative Medicine/ Integrative Medicine) provide a contribution? (Value creation and delivery)
• CAM uses different concepts > CAM sees/looks different > CAM acts different. (Specific contribution)
• The contribution should be of good quality. (Evidence-based)
• An organization network of practice, research and civil society actors and a long-term program is necessary to demonstrate/ realize/ deliver the CAM contribution. (Organization)
Quality of the CAM/ IM contribution
• Quality of the concepts: – Basic concepts
– Prevention strategies concepts
– Treatment strategies concepts
• Quality criteria of concepts: – Internal consistency
– In agreement with other, accepted theories – In agreement with empirical facts
Quality of the CAM/ IM contribution
• Health & disease (in general, specific: infections)
• Fighting disease vs. health promotion– New internal consistent concepts of health (‘the ability to
adapt and self manage’ (Huber et al., 2011)/ ‘self regulation’ (Baars et al., 2011)/ ‘salutogenesis’ (Mittelmark et al., 2017 ) in line with CAM conceptualization of health
– Increasingly consistent with other relevant concepts
– Increasingly empirically testedHuber M, et al. (2011). How should we define health?. BMJ, 343.
Baars EW (2011). Evidence-based curative health promotion: a systems biology-orientated treatment of seasonal allergic rhinitis with Citrus/Cydonia comp., Wageningen University.
Mittelmark MB, et al. (2017). The Handbook of Salutogenesis. Springer International Publishing.
Quality of the CAM/ IM contribution
• Quality of the: – Basic concepts
– Prevention strategies
– Treatment strategies
Quality of the CAM/ IM contribution
• Quality of the: – Concepts
– Prevention strategies: is there evidence of • Restricted use of antibiotics and antipyretics in infections
• Benefits of fever
• ….
– Treatment strategies
Antibiotic prescription CAM GP practice
IIPCOS Study International Integrative Primary Care Outcomes Study
Antibiotic prescription AM GP practice
0 10 20 30 40
Antihistamines
Anti-inflammatory agents
Cough and cold prep.
Nasal preparations
Analgesics
Antibacterials
Percentage
Anthroposophy
Conventional
• Five countries: AT, GE, NL, UK, US
• N = 1.016 outpatients
Antibiotic resistance in AM hospitals
Multiresistant bacteria PH Hospitals Germany
MRSA 19 % 21,3 %
MRSA in clinic acquired/1000 Pt p. day 0 0,16
VRE (vancomycine res. enterococ) 0,4 % 12,6 %
Pseudomonas, Imipenem-res. 7,7 % 16,8 %
3 and 4 - MRGN E. coli (ESBL) 1,2 % 10,4 %
Antibiotics resistance rates in anthroposophic clinics
Example: Paracelsus hospital, Bad Liebenzell 2000 ambulatory patients p.d.
60% referral from CAM doctors/ 40% Tumor patients / 10% Palliative patients
External infectiology monitoring by hospital hygiene dpt., University Freiburg 2014
Mortality in mammals with severe infection
Shann, Lancet 1995
“Overall, treatment with antipyretics probably increases mortality in severe infection, and may prolong viral shedding and impair the antibody responses to viral infection. "
Study: Antipyresis in Experimental Influenza A and Shigella sonnei Infections in adults
Plaisance et. al, Pharmacotherapy 2000
0 1 2 3 4 5 6 7 8 9 10 11 12
InfluenzaA
Shigellasonnei
Duration of disease (days)
with antipyresis
without antipyresis
Quality of the CAM contribution
• Quality of the: – Concepts
– Prevention strategies
– Treatment strategies: is there evidence of safety and efficacy/ effectiveness in:
• In-vitro studies
• Observational studies/ RCTs
• Systematic reviews/ meta-analyses
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Effects of Berberis cortex on bacterial growth of Staphylococcus aureus strains.
Bacterial growth after 0, 4, 8 and 24 hours on logarithmic scale. Control sample DW (distilled
water) and test sample Berberis Decoctum D2 were added in a ratio of 1:2 to the culture medium.
Bactericidal effects are visible for all S.aureus strains. MIC 5mg/ml
Roser E. Inaug Diss Freiburg 2015
Antibacterial activity of Berberis cortex extract
Antibiotic prescription AM GP practice
0 10 20 30 40
Antihistamines
Anti-inflammatory agents
Cough and cold prep.
Nasal preparations
Analgesics
Antibacterials
Percentage
Anthroposophy
Conventional
Herbal medicines for respiratory tract infection
• Antibiotics prescribed for viral upper respiratory tract infection (URTI) in primary care major source of inappropriate prescribing
• Several herbs promising evidence • Enhance innate immune system (NK cells,
macrophages) • Anti-inflammatory • Direct antiviral activity
Andrographis paniculata leaf for upper respiratory tract
(Kan Jang, Indian Echinacea)
•Seven RCTs •n = 896 • Superior to placebo for acute treatment • Preliminary evidence of preventative effect • Adverse effects mild and infrequent
Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Coon JT, Ernst E, Planta Med 2004; 70: 293-8.
Herbs with systemic�antimicrobial
potential: Alchornea cordifolia
• Reported activity against pathogenic microorganisms, including: • Aspergillus • E coli
• H pylori
• Klebsiella
• Proteus spp
• Pseudomonas
• Salmonella spp
Herbs with systemic antimicrobial
potential: �Bidens bipinnata
• Reported activity against pathogenic microorganisms, including: • Bacillus spp • Klebsiella
• Leishmania amazonensis
• M tuberculosis
• N gonorrhoeae
• Pseudomonas
• Staph aureus
Herbs with systemic antimicrobial�
potential:
Crytolepis sanguinolenta
• Reported activity against pathogenic microorganisms, including: • Aspergillus
• Babesia spp
• Campylobacter spp
• N gonorrhoeae
• P malariae
• Staph aureus
Herbs with systemic antimicrobial
potential: �Sida acuta
• Reported activity against pathogenic microorganisms, including: • Bacillus spp • E coli
• H pylori
• Klebsiella
• Pseudomonas
• Salmonella spp
• Staph aureus
• Vibrio
RCTs & herbal medicines
ATAFUTI
Alternative Treatment for Adult Female Urinary Tract Infection: a double blind randomized controlled trial.
Funder: National School of Primary Care Research (NSPCR) Collaboration between University of Southampton, University of Bristol and University of Oxford
Principal Investigator: Professor Michael Moore, University of Southampton
Co-investigator: Professor Alastair Hay
Study Manager Bristol: Dr Esther Kok
Study Coordinator Bristol: Dr Victoria Wilson
Recruitment start date nationally: August 2015
Trial Objectives
Two candidates for symptom relief for UTI have been identified: 1. Ibuprofen
Shown in one small study to provide good symptom relief in UTI with only 33% of participants requiring antibiotics.
2. Uva Ursi
Known as bearberry, a herbal product which has been used as a traditional treatment for urine infections.
Primary objective:
To compare whether ibuprofen or Uva Ursi provide relief from urinary symptoms in adult women with a suspected UTI.
Secondary objective: Do ibuprofen or Uva Ursi result in reduced antibiotic uptake
Cochrane reviews & protocolsReview & approved protocols Area Cochrane Group Chinese medicinal herbs for acute bronchitis Bronchitis Acute respiratory infections Chinese medicinal herbs for the common cold Coryza Acute respiratory infections Over-the-counter (OTC) medications for acute cough in children and adults in community settings
Coryza Acute respiratory infections
Honey for acute cough in children Coryza Acute respiratory infections Garlic for the common cold Coryza Acute respiratory infections Echinacea for preventing and treating the common cold Coryza Acute respiratory infections Chinese medicinal herbs for sore throat Sore Throat Acute respiratory infections Pelargonium sidoides extract for treating acute respiratory tract infections
RTI Acute respiratory infections
Probiotics for preventing acute upper respiratory tract infections
RTI Acute respiratory infections
Homeopathic Oscillococcinum® for preventing and treating influenza and influenza‐like illness
RTI Acute respiratory infections
Zinc supplements for preventing otitis media ear Acute respiratory infections Zinc supplements for preventing otitis media ear Acute respiratory infections Xylitol for preventing acute otitis media in children up to 12 years of age
ear Acute respiratory infections
Vitamin C for preventing and treating pneumonia pneumonia Acute respiratory infections Over -the -counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults
pneumonia Acute respiratory infections
Chinese herbs combined with Western medicine for severe acute respiratory syndrome (SARS)
SARS Acute respiratory infections
Chinese herbal medicine Huangqi type formulations for nephrotic syndrome
Renal Renal
Cranberries for preventing urinary tract infections UTI Renal
Cranberries for the treatment of urinary tract infections
UTI Renal
Probiotics for preventing urinary tract infections in adults and children
UTI Renal
Chinese herbal medicine for treating recurrent urinary tract infections in women.
UTI Renal
Chinese herbal medicines for treating skin and soft-tissue infections
Skin Wounds
Quality of the CAM contribution
• (Systematic) reviews/ meta-analyses (state of the art):– Review by Hufelandgesellschaft
Quality of the CAM contribution
Urinary infections
Gastrointestinal infections
Respiratoryinfections
Anthroposophic Medicine + = +
Homeopathy ø ø +Naturopathy/Phythotherapy + ++ = / +TCM = = +Ayurvedic Medicine ø = =Other CAM-methods:Probiotics, �Fecal Microbiotica Transplantation (FMT)
+ +++
= / +
+ higher efficacy (Outcome, duration and severity of symptoms, side effects)
- worse efficacy
= same efficacy
Ø no data
Preliminary results: Short overview
Quality of the CAM contribution
• (Systematic) reviews/ meta-analyses (state of the art)– Review by international CAM/IM consortium on position &
contribution of CAM/IM
Quality of the CAM/ IM contribution: summary
• Quality of the concepts: – Basic concepts:
• Internal consistent
• Increasingly in agreement with other accepted theories and empirical facts
– Prevention and treatment strategies concepts: • Contributing to policy of:
– Less antibiotics prescription & consumption
– Appropriate use of antibiotics
– Alternatives for antibiotics
• Increasingly tested
• Increasingly evidence-based
• More research needed
• More communication needed
• More implementation needed
Four perspectives
• Worldwide problem: can CAM/IM (Complementary & Alternative Medicine/ Integrative Medicine) provide a contribution? (Value creation and delivery)
• CAM uses different concepts > CAM sees/looks different > CAM acts different. (Specific contribution)
• The contribution should be of good quality. (Evidence-based)
• An organization network of practice, research and civil society actors and a long-term program is necessary to demonstrate/ realize/ deliver the CAM contribution. (Organization)
Elements of an integrative program
In general• Priorities list of stakeholders (questions)
• Evidence on contribution of CAM/IM (value creation)
• Communication & implementation (value delivery)
Specific projects• JPIAMR
• Horizon2020
Elements of an integrative program
• Priorities lists of demands of different stakeholders:– Public health and doctors:
• Infectious diseases where antibiotics are not indicated.• Infectious diseases where the resistance problem is very large: e.g.,
bacterial urinary tract infections, enteritis and upper respiratory infections.
• Infectious diseases in countries with not enough antibiotics.• Trainings for professionals• …
– Patients: • Alternative strategies for infectious diseases of, for example, children.• Trainings for parents and selfmanagement• ….
– ….
Elements of an integrative program
Current state of the art• Description of the specific contribution of CAM/IM (concept development;
value creation), underpinned by:
• Testing of concept on agreement with related, accepted concepts
• (Syst.) reviews/ meta-analyses (state of the art empirical evidence):– Direct evidence:
• Best practices/ clinical expertise• In-vitro studies• RCT and observational studies on safety, efficacy/ effectiveness, costs
– Indirect evidence: • Antibiotic prescription rates in conventional and CAM GP practices and hospitals• Antibiotic resistance rates in conventional and CAM hospitals• Client experiences
Elements of an integrative research program
Prevention strategies• Effect Parental Fever-Training on use of antipyretics and
antibiotics• Effects lifestyle and infection prevention• ……
Elements of an integrative research program
Treatment strategies• Collecting best practices/ clinical expertise:
– Case reports – Surveys
– ….
• In-vitro research:– Safety
– Effects/ mode of actions
– Side-effects/ toxicity
– Optimal dosing
– Effects of pharmaceutical procedures – …..
Elements of an integrative program
Treatment strategies • Monodisciplinary treatments for indications• Multimodal treatments for specific indications• Interactions with antibiotics• …..
• Effects on:– Symptom relief/ symptom reduction
– Antibiotic prescription and consumption
– Self-regulation capacity/ immune system
– Resistance levels
– ….
Elements of an integrative program
Communication• International website: overview and update information
• Trainings – e.g.: development, realization and evaluation of an
anthroposophic training program for nurses and other health care professionals to enable them to counsel parents. Parent programs > less AB and antipyretics prescriptions. Guideline development alternative treatments of infections.
• Multi-stakeholder oriented
Elements of an integrative program
• JPIAMR grant “Appropriate use of antibiotics: the role of CAM treatment strategies” (January 2017 – July 2018)
• Aims:– To provide an overview of expert and scientific knowledge (best
practices) on CAM/IM treatment of infectious diseases where: • ABs are not indicated• The resistance problem is very large:
– Bacterial UTIs– Bacterial GIIs– URIs
– To develop a decision making tool, incl. guidelines for conventional and CAM/IM practitioners
– To provide a communication platform
– To explore possible implementation routes
Elements of an integrative program
General aims of the program (tentative)• Evaluating the potential of the CAM/ IM strategies (prevention and symptom relief
strategies, alternative treatment to antibiotics, appropriate use of antibiotics (reduction of prescription and consumption of antibiotics).
• Bridging the knowledge / expertise of conventional experts and CAM/ IM experts regarding risk management and reduction of prescription- and consumption rates.
• Deepening the knowledge in this CAM/ IM domain.• Evaluating and deepening knowledge about socio-economic factors determining the
antibiotics use.• Providing tools for further dissemination of evidence-based CAM/ IM knowledge in
clinical practice and society.• Providing an educational tool leading to appropriate use of antibiotics in general practice
and hospitals.• Evaluating training modules (medical professionals and parents/ patients) regarding CAM
prevention and treatment aiming at reducing prescription and consumption of antibiotics.