antimicrobial resistance an integrative research perspective … · antimicrobial resistance an...

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)

The problem

The problem

•  Drug resistance

•  Historical development

•  The burden of the problem

•  Policy

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



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alternative to penicillin for the treatment of S. aureus in Boston City Hospital in the early 1950s, it was completely withdrawn after less than a year because 70% of all the S. aureus isolates were found to have become erythromycin resistant.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)



Mechanisms of resistance

•  Mechanisms of resistance:

–  Genetic

–  Biochemical

–  ..

•  Examples: –  The formation of microbial biofilms


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.


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.

The burden

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

Policy

Source: Wilson, D. N. (2014). Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology, 12(1), 35-48.

Policy

Policy

RAND Recommendations for the next 5 years

EU AMR Action Plan

Policy

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


•  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


•  Is there a contribution of CAM/IM?


•  Can CAM/IM provide innovative strategies aiming at :

–  Less antibiotics prescription & consumption

–  Appropriate use of antibiotics


Four perspectives





The specific contribution of CAM/ IM


•  What is next in the row?

32, 38, 44, 48, 56, 60, ?



32, 38, 44, 48, 56, 60, ‘Meadowlark’



32, 38, 44, 48, 56, 60, ‘Meadowlark’

The next station after 60th street


•  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.


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.


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.


•  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)


•  Concepts

•  Prevention strategies

•  Treatment strategies


•  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


•  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.


•  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





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


•  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: –  Basic concepts

–  Prevention strategies

–  Treatment strategies


•  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 AM GP practice

Antibiotic prescription CAM GP practice

IIPCOS Study International Integrative Primary Care Outcomes Study


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. "

[email protected]

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

[email protected]

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


0 10 20 30 40

Antihistamines

Anti-inflammatory agents

Cough and cold prep.

Nasal preparations

Analgesics

Antibacterials

Percentage

Anthroposophy

Conventional


Odds Ratio > 1: in favor of AM treatment

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.

Pelargonium sidiodes for acute bronchitis

Cranberry for UTIs

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

Reviews

http://www.cam-europe.eu/dms/

files/Position_Papers

/

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


Homeopathic Oscillococcinum® for preventing and treating influenza and influenza‐like illness


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


•  (Systematic) reviews/ meta-analyses (state of the art):–  Review by Hufelandgesellschaft


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


•  (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


•  Increasingly tested

•  Increasingly evidence-based

•  More research needed

•  More communication needed

•  More implementation needed

Four perspectives





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


•  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•  ….

–  ….


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 –  …..


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

–  ….


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


•  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


•  Currently the consortium is preparing a Horizon2020 proposal


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.

Thank you very much for your attention!

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